Novel use of phenylheteroakylamine derivatives

ABSTRACT

There is disclosed the use of a compound of formula (I) wherein R 1 , R 2 , X, Y, V, W and Z are as defined in the specification, and pharmaceutically acceptable salts, enantiomers or racemates thereof, in the manufacture of a medicament, for the treatment or prophylaxis of diseases or conditions in which inhibition of nitric oxide synthase activity is beneficial. Certain novel compounds of formula (Ia) and pharmaceutically acceptable salts thereof, and enantiomers and racemates thereof are disclosed; together with processes for their preparation, compositions containing them and their use in therapy. The compounds of formulae (I) and (Ia) are inhibitors of the enzyme nitric oxide synthase and are thereby particularly useful in the treatment or prophylaxis of inflammatory disease.

FIELD OF THE INVENTION

[0001] The present invention relates to the use ofphenylheteroalkylamine derivatives as inhibitors of the enzyme nitricoxide synthase. Certain novel phenylheteroalkylamine derivatives arealso disclosed together with processes for their preparation,compositions containing them and their use in therapy.

BACKGROUND OF THE INVENTION

[0002] Nitric oxide is produced in mammalian cells from L-arginine bythe action of specific nitric oxide synthases (NOSs). These enzymes fallinto tro distinct classes—constitutive NOS (cNOS) and inducible NOS(iNOS). At the present time, two constitutive NOSs and one inducible NOShave been identified. Of the constitutive NOSs, an endothelial enzyme(ecNOS) is involved with smooth muscle relaxation and the regulation ofblood pressure and blood flow, whereas the neuronal enzyme (ncNOS)serves as a neurotransmitter and appears to be involved in theregulation of various biological functions such as cerebral ischaemia.Inducible NOS has been particularly implicated in the pathogenesis ofinflammatory diseases. Regulation of these enzymes should thereforeoffer considerable potential in the treatment of a wide variety ofdisease states (J. E. Macdonald, Ann. Rep. Med . Chem., 1996, 31,221-230).

[0003] Considerable effort has been expended in efforts to identifycompounds that act as specific inhibitors of one or more isoforms of theenzyme nitric oxide synthase. The use of such compounds in therapy hasalso been widely claimed.

[0004] Patent application EP 0 273 658 discloses compounds of formula

[0005] wherein Ar represents phenyl optionally substituted by halogen,C1 to 4 alkyl, C1 to 3 alkoxy or CF₃, or optionally substitutednaphthyl; R¹ represents C5 to 7 cycloalkyl, thienyl, halothienyl, (C1 to4 alkyl)-substituted-thienyl, furanyl, pyridyl or thiazolyl; and R² andR³ are each independently H or methyl. Said compounds are potent andselective inhibitors of serotonin and norepinephrine uptake and arethereby stated to be useful in the treatment of human diseases such asanxiety, depression and obesity.

[0006] U.S. Pat. No. 4,314,081 discloses compounds of formula

[0007] wherein Ar represents phenyl optionally substituted by halogen,C1 to 4 alkyl, C1 to 3 alkoxy or C3 to 4 alkenyl; or Ar representsnaphthyl; and R¹, R² and R³ are each independently H or methyl. Saidcompounds are potent and selective inhibitors of serotonin andnorepinephrine uptake and are thereby stated to be useful in thetreatment of human diseases such as depression and obesity.

[0008] Patent application WO 92/19210 discloses compounds of formula

[0009] wherein Ar¹ and Ar² independently represent phenyl optionallysubstituted by various substituents but with the proviso that at leastone of Ar¹ and Ar² is substituted by at least one halogen atom; and R¹and R² are each independently H or C1 to 4 alkyl. Said compounds arestated to be useful for imaging neurotransmitter re-uptake systems inthe brain.

[0010] Patent application DE 29 07 217 discloses compounds of formula

[0011] wherein Ar¹ represents phenyl substituted by nitro and optionallysubstituted by a second substituent selected from Cl, Br, CF₃, Me orOMe; Ar² represents phenyl optionally substituted by Cl, Br or F; R¹represents H or C1 to 5 alkyl; and R² represents C1 to 5 alkyl. Thecompounds are stated to be useful in the treatment of eating disordersand depression.

[0012] Patent application GB 2 060 620 discloses compounds of formula

[0013] wherein Ar¹ represents phenyl optionally substituted by C1 to 6alkyl, C2 to 6 alkenyl, CF_(3,) halogen, nitro, amino or acylamino; Arrepresents phenyl substituted by at least one group selected from C1 to6 alkyl, C1 to 6 alkoxy, CF₃, nitro or amino; R¹, R² and R⁴independently represent H or C1 to 6 alkyl; and R³ represents H, C1 to 6alkyl or benzyl. The compounds are claimed to be useful asantidepressants.

[0014] Patent application GB 2 060 621 discloses compounds of formula

[0015] wherein Ar represents phenyl optionally substituted by C1 to 6alkyl or halogen; Ar¹ represents phenyl substituted by NO₂, amino oracylamino; R¹ and R² independently represent H or C1 to 6 alkyl. Thecompounds are claimed to be useful as antidepressants.

[0016] Patent application EP 3 18 727 discloses compounds of formula

[0017] wherein R¹ can represent optionally substituted alkyl orcycloalkyl and R² can represent optionally substituted phenyl. Thecompounds prevent calcium overload in brain cells and are thus useful inthe treatment of anoxia, migraine, ischaemia and epilepsy.

[0018] Patent application EP 399 504 discloses compounds of formula

[0019] wherein Ar represents optionally substituted phenyl; R can alsorepresent optionally substituted phenyl; and R¹ and R² can representoptionally substituted alkyl or cycloalkyl. The compounds preventcalcium overload in brain cells and are thus useful in the treatment ofanoxia, migraine, ischaemia and epilepsy.

[0020] Patent application EP 576 766 discloses compounds of formula

[0021] wherein Ar represents optionally substituted phenyl; R can alsorepresent optionally substituted phenyl; R¹ and R² can representoptionally substituted alkyl or cycloalkyl; or the group NR¹R²represents a 5 to 7 membered ring, optionally further substituted. Thecompounds prevent calcium overload in brain cells and are thus useful inthe treatment of anoxia, traumatic injury, neurodegenerative diseases,migraine, ischaemia and epilepsy.

[0022] Patent application EP 571 685 discloses compounds similar tothose of EP 576 766 but wherein Ar represents optionally substitutedfuranyl, thienyl or pyrrolyl.

[0023] The present invention relates to the surprising finding that agroup of phenylheteroalkylamine derivatives, including some compoundsthat are within the generic scopes of some of the above background artdocuments, are inhibitors of the enzyme nitric oxide synthase.

DISCLOSURE OF THE INVENTION

[0024] According to the present invention, there is provided the use ofa compound of formula (I)

[0025] wherein:

[0026] X and Y independently represent C1 to 4 alkyl, C1 to 4 alkoxy,halogen, CF₃, OCF₃, CN, C≡CH, S(O)_(m)CH₃, S(O)_(p)CF₃, NO₂ or NHCHO;

[0027] m and p independently represent an integer 0, 1 or 2;

[0028] Z represents H or fluoro;

[0029] V represents O;

[0030] W represents phenyl or a five or six membered aromaticheterocyclic ring containing 1 to 3 heteroatoms independently selectedfrom O, S and N; said phenyl or aromatic heterocyclic ring beingoptionally substituted by one or more substituents selectedindependently from halogen, C1 to 4 alkyl, C1 to 4 alkoxy, OH, CN, NO₂or NR⁴R⁵; said alkyl or alkoxy group being optionally furthersubstituted by one or more fluorine atoms;

[0031] R¹ and R² independently represent H, C1 to 4 alkyl or C3 to 6cycloalkyl; said alkyl group is being optionally substituted by C1 to 4alkoxy, halogen, hydroxy, NR⁶R⁷, phenyl or a five or six memberedaromatic or saturated heterocyclic ring containing 1 to 3 heteroatomsindependently selected from O, S and N; said phenyl or aromaticheterocyclic ring being optionally firther substituted by halogen, C1 to4 alkyl, C1 to 4 alkoxy, CF₃, OCF₃, CN or NO₂;

[0032] or the group NR¹R² together represents a 4 to 8 memberedsaturated azacyclic ring optionally incorporating one firther heteroatomselected from O, S or NR⁸; said ring being optionally substituted by C1to 4 alkyl, C1 to 4 alkoxy or OH; said alkyl group being optionallysubstituted by C1 to 4 alkoxy, OH or NR⁹R¹⁰;

[0033] or the group NR¹R² together represents part of a five memberedaromatic azacyclic ring optionally incorporating one fuirther N atom;

[0034] R⁴, R⁵, R⁶, R⁷, R⁹ and R¹⁰ independently represent H or C1 to 4alkyl;

[0035] R⁸ represents H or C1 to 6 alkyl; said alkyl group beingoptionally substituted by C1 to 4 alkoxy, OH, NR¹¹R¹², phenyl or a fiveor six membered aromatic or saturated heterocyclic ring containing 1 to3 heteroatoms independently selected from O, S and N; said phenyl oraromatic heterocyclic ring being optionally further substituted byhalogen, C1 to 4 alkyl, C1 to 4 alkoxy, CF₃, OCF₃, CN or NO₂;

[0036] R¹¹ and R¹² independently represent H or C1 to 4 alkyl;

[0037] or a pharmaceutically acceptable salt, enantiomer or racematethereof, in the manufacture of a medicament, for the treatment orprophylaxis of diseases or conditions in which inhibition of nitricoxide synthase activity is beneficial.

[0038] In another aspect the invention provides the use of a compound offormula (I) or a pharmaceutically acceptable salt, enantiomer orracemate thereof, in the manufacture of a medicament, for the treatmentor prophylaxis of diseases or conditions in which inhibition of theinducible isoform of the enzyme nitric oxide synthase activity isbeneficial.

[0039] A more particular aspect of the invention provides the use of acompound of formula (I) or a pharmaceutically acceptable salt,enantiomer or racemate thereof, in the manufacture of a medicament, forthe treatment or prophylaxis of inflamrnatory disease.

[0040] According to the invention, there is also provided a method oftreating, or reducing the risk of, diseases or conditions in whichinhibition of nitric oxide synthase activity is beneficial whichcomprises administering to a person suffering from or at risk of, saiddisease or condition, a therapeutically effective amount of a compoundof formula (I) or a pharmaceutically acceptable salt, enantiomer orracemate thereof.

[0041] Further, according to the invention, there is also provided amethod of treating, or reducing the risk of, diseases or conditions inwhich inhibition of the activity of the inducible isoform of the enzymenitric oxide synthase is beneficial, which comprises administering to aperson suffering from or at risk of, said disease or condition, atherapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable salt, enantiomer or racemate thereof.

[0042] More particularly, there is also provided a method of treating,or reducing the risk of, inflammatory disease in a person suffering fromor at risk of, said disease, wherein the method comprises administeringto the person a therapeutically effective amount of a compound offormula (I) or a pharmaceutically acceptable salt, enantiomer orracemate thereof.

[0043] In another aspect the invention provides a pharmaceuticalformulation comprising a therapeutically effective amount of a compoundof formula (I), or a pharmaceutically acceptable salt, enantiomer orracemate thereof, in admixture with a pharmaceutically acceptableadjuvant, diluent or carrier, for use in the treatment or prophylaxis ofdiseases or conditions in which inhibition of nitric oxide synthaseactivity is beneficial.

[0044] In another preferred aspect the invention provides apharmaceutical formulation comprising a therapeutically effective amountof a compound of formula (I), or a pharmaceutically acceptable salt,enantiomer or racemate thereof, in admixture with a pharmaceuticallyacceptable adjuvant, diluent or carrier, for use in the treatment orprophylaxis of diseases or conditions in which inhibition of theinducible isoform of the enzyme nitric oxide synthase activity isbeneficial.

[0045] In another more particular aspect the invention provides apharmaceutical formulation comprising a therapeutically effective amountof a compound of formula (I), or a pharmaceutically acceptable salt,enantiomer or racemate thereof, in admixture with a pharmaceuticallyacceptable adjuvant, diluent or carrier, for use in the treatment orprophylaxis of inflammatory disease.

[0046] The compounds of formula (I) may also be used advantageously incombination with a second pharmaceutically active substance,particularly in combination with a selective inhibitor of the inducibleisoform of cyclooxygenase (COX-2). Thus, in a further aspect of theinvention there is provided the use of a compound of formula (I) or apharmaceutically acceptable salt, enantiomer or racemate thereof, incombination with a COX-2 inhibitor for the treatment of inflammation,inflammatory disease and inflammatory related disorders. And there isalso provided a method of treating, or reducing the risk of,inflammation, inflammatory disease and inflammatory related disorders ina person suffering from or at risk of, said disease or condition,wherein the method comprises administering to the person atherapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable salt, enantiomer or racemate thereof incombination with a COX-2 inhibitor.

[0047] In one preferred embodiment, X and Y independently represent Br,Cl, CH₃, CF₃ or CN. It is particularly preferred that X represents Br,Cl or CF₃. It is also particularly preferred that Y represents Cl or CN.

[0048] Preferably, W represents an optionally substituted five or sixmembered aromatic heterocyclic ring containing 1 to 3 heteroatomsindependently selected from O, S and N. Particular examples are thosewherein W represents thienyl, furyl, pyridyl, thiazolyl, oxazolyl,isoxazolyl or pyrimidyl.

[0049] Preferably, R¹ and R² independently represent H or C1 to 4 alkyloptionally substituted by C1 to 4 alkoxy or hydroxy. More preferably, R¹and R² independently represent H or methyl.

[0050] The use of the following compounds of formula (I) andpharmaceutically acceptable salts, enantiomers or racemates thereof isspecifically included within the invention:

[0051] 2-(3-amino-1-phenylpropoxy)-4-chlorobenzonitrile;

[0052] 4-chloro-2-(3-(methylamino)-1-phenylpropoxy)benzonitrile;

[0053] 4-bromo-2-[( 1 R)-3-(Methylamino)-1-phenylpropoxy]benzonitrile;

[0054] γ-R-(2-bromo-5-chlorophenoxy)-N-methylbenzenepropanamine;

[0055] 4-chloro-2-{[(1R)-3-chloro-1-phenylpropyl]oxy}benzonitrile;

[0056]4-methoxy-2-[3-(methylamino)-1-phenylamino-1-phenylpropoxy]benzonitrile;

[0057]4-methyl-2-{[(1R)-3-(methylamino)-1-phenylpropyl]oxy}benzonitrile;

[0058] R-γ-(2,5-dichlorophenoxy)-N-methyl-2-thiophenepropanainine;

[0059] S-γ-(2,5-dichlorophenoxy)-N-methyl-2-thiophenepropanamine;

[0060]2-[[(3R)-3-(2,5-dichlorophenoxy)-3-(2-thienyl)propyl]amino]ethanol;

[0061]4-chloro-2-{[(1R)-3-(4-methyl-1-piperazinyl)-1-phenylpropyl]oxy}-benzonitrile;

[0062] 4-chloro-2-{[(1R)-3-(4-hydroxy-1-piperidinyl)-1-phenylpropyl]oxy}-benzonitrile;

[0063]4-chloro-2-{[(1R)-3-[(2-hydroxyethyl)methylamino]-1-phenylpropyl]oxy}-benzonitrile;

[0064]4-chloro-2-{[(1R)-3-(4-morpholinyl)-1-phenylpropyl]oxy}-benzonitrile;

[0065]4-chloro-2-{[(1R)-3-[(3R)-3-hydroxypyrrolidinyl]-1-phenylpropyl]oxy}-benzonitrile;

[0066]4-chloro-2-{[(1R)-3-[(3S)-3-hydrokypyrrolidinyl]-1-phenylpropyl]oxy}-benzonitrile;

[0067]2-{[(1R)-3-amino-1-phenylpropyl]oxy}-5-fluoro-4-methylbenzonitrile;

[0068]4-chloro-5-fluoro-2-[3-(methylamino)-1-(2-pyrimidinyl)propoxy]benzonitrile;

[0069]4-chloro-5-fluoro-2-({(1R)-1-(3-furanyl)-3-[(2-methoxyethyl)amino]propyl}oxy)benzonitrile;

[0070]4-methoxy-2-[[(1R)-3-(methylamino)-1-phenylpropyl]oxy]-benzonitrile;

[0071] γ-(2-bromo-5-fluorophenoxy)-N-methyl-benzenepropanamine;

[0072] (R)-γ-(5-bromo-2-chlorophenoxy)-N-methylbenzenepropanamine;

[0073] (R)-γ-(2-bromo-5-nitrophenoxy)-N-methylbenzenepropanamine;

[0074]4-chloro-5-fluoro-2-[[(1R)-3[(2-methoxyethyl)amino]-1-phenylpropyl]oxy]-benzonitrile;

[0075]4-chloro-2-{[(1R)-3-(cyclopropylamino)-1-phenylpropyl]oxy}-5-fluorobenzonitrile;

[0076]4-chloro-2-{[(1R)-3-(cyclopropylamino)-1-(3-furanyl)propyl]oxy}-5-fluorobenzonitrile;

[0077]4-chloro-2-{[(1R)-3-(cyclopropylamino)-1-(3-thienyl)propyl]oxy}-5-fluorobenzonitrile;

[0078]4-bromo-2-{[(1R)-3-(cyclopropylamino)-1-(phenyl)propyl]oxy}-5-fluorobenzonitrile;

[0079]4-bromo-2-{[(1R)-3-(cyclopropylamino)-1-(3-furanyl)propyl]oxy}-5-fluorobenzonitrile;

[0080]4-bromo-2-{[(1R)-3-(cyclopropylamino)-1-(3-thienyl)propyl]oxy}-5-fluorobenzonitrile;

[0081]4-chloro-5-fluoro-2-({(1R)-3-[(3-hydroxypropyl)amino]-1-phenylpropyl}oxy)benzonitrile;

[0082]4-chloro-5-fluoro-2-{[(1R)-1-(3-furanyl)-3-(3-hydroxypropyl)amino]propyl]oxy}benzonitrile;

[0083]4-chloro-5-fluoro-2-{[(1R)-3-[(3-hydroxypropyl)amino]-1-(3-thienyl)propyl]oxy}benzonitrile;

[0084]4-bromo-5-fluoro-2-({(1R)-3-[(3-hydroxypropyl)amino]-1-phenylpropyl}oxy)benzonitrile;

[0085]4-bromo-5-fluoro-2-({(1R)-1-(3-furanyl)-3-[(3-hydroxypropyl)amino]propyl}oxy)benzonitrile;

[0086]4-bromo-5-fluoro-2-{[(1R)-3-[(3-hydroxypropyl)amino]-1-(3-thienyl)propyl]oxy}benzonitrile;

[0087]2-[[(1R)-3-amino-1-phenylpropyl]oxy]-4-(trifluoromethyl)benzonitrile;

[0088] 2-[[(1R)-3-amino-1-phenylpropyl]oxy]-4-chlorobenzonitrile;

[0089]4-chloro-5-fluoro-2-[[(1R)-3-(methylamino)-1-phenylpropyl]oxy]benzonitrile;

[0090]2-[[(1R)-3-amino-1-phenylpropyl]oxy]-4-chloro-5-fluorobenzonitrile;

[0091]γ-[5-chloro-2-(trifluoromethyl)phenoxy]-N-methylbenzenepropanamine;

[0092]2-[[(1R)-3-(methylamino)-1-phenylpropyl]oxy]-4-(trifluoromethyl)benzonitrile;

[0093]4-chloro-5-fluoro-2-[[(1R)-3-[[(5-methylpyrazinyl)methyl]amino]-1-phenylpropyl]oxy]benzonitrile;

[0094]4-chloro-5-fluoro-2-[[(1R)-3-[(1H-imidazol-2-ylmethyl)amino]-1-phenylpropyl]oxy]benzonitrile;

[0095]4-chloro-2-[[(1R)-3-[[2-(dimethylamino)ethyl]amino]-1-phenylpropyl]oxy]-5-fluorobenzonitrile;

[0096]4-chloro-5-fluoro-2-[[(1R)-3-[[2-(4-morpholinyl)ethyl]amino]-1-phenylpropyl]oxy]benzonitrile;

[0097]4-chloro-5-fluoro-2-[[(1R)-3-[[2-(1H-imidazol-1-yl)ethyl]amino]-1-phenylpropyl]oxy]benzonitrile;

[0098]4-chloro-5-fluoro-2-[[(1R)-3-[[2-(1H-imidazol-4-yl)ethyl]amino]-1-phenylpropyl]oxy]benzonitrile;

[0099] 4-chloro-5-fluoro-2-[[(1R)-3-[(2-hydroxyethyl)amino]-1-phenylpropyl]oxy]benzonitrile;

[0100]2-[[(1R)-3-[(2-aminoethyl)amino]-1-phenylpropyl]oxy]-4-chloro-5-fluorobenzonitrile;

[0101]4-chloro-5-fluoro-2-[[(1R)-1-phenyl-3-[(3,3,3-trifluoropropyl)amino]propyl]oxy]benzonitrile;

[0102] 2-{[(1R)-3-amino-1-(2-thiazolyl)propyl]oxy}-4-chlorobenzonitrile;

[0103]4-chloro-2-{[(1R)-3-(methylamino)-1-(2-thiazolyl)propyl]oxy}benzonitrile;

[0104] (R)-γ-(2,5-dichlorophenoxy)-2-thiazolepropanamine;

[0105] 2-[3-amino-1-(2-oxazolyl)propoxy]-4-chlorobenzonitrile;

[0106] γ-(2,5-dichlorophenoxy)-2-oxazolepropanamine;

[0107]2-[[-3-amino-1-(3-pyridinyl)propyl]oxy]-4-chloro-5-fluorobenzonitrile;

[0108]4-chloro-5-fluoro-2-[3-(methylamino)-1-(3-pyridinyl)propoxy]benzonitrile;

[0109] γ-[2-chloro-5-(trifluoromethyl)phenoxy]-3-pyridinepropanamine;

[0110]2-[3-amino-1-(6-methoxy-2-pyridinyl)propoxy]-4-chloro-5-fluorobenzonitrile;

[0111]2-[3-amino-1-(1,6-dihydro-6-oxo-2-pyrdinyl)propoxy]-4-chloro-5-fluorobenzonitrile;

[0112] 2-[3-amino-1-(6-bromo-3-pyridinyl)propoxy]-4-chlorobenzonitrile;

[0113] 2-[[3-amino-1-(5-isoxazolyl)propyl]oxy]-4-chlorobenzonitrile;

[0114]4-chloro-2-[3-[(2-hydroxyethyl)amino]-1-(5-isoxazolyl)propoxy]benzonitrile;

[0115] (R)-γ-(2,5-dichlorophenoxy)-5-isoxazolepropanamine;

[0116] (R)-γ-(2,5-dichlorophenoxy)-N-methyl-benzenepropanamine;

[0117](R)-γ-[2-chloro-5-(trifluoromethyl)phenoxy]-N-methyl-benzenepropanamine;

[0118]4-chloro-2-[[(1R)-3-(methylamino)-1-(2-thienyl)propyl]oxy]benzonitrile;

[0119]2-[[(1R)-3-amino-1-(3-furanyl)propyl]oxy]-4-chloro-5-fluorobenzonitrile;

[0120]4-chloro-5-fluoro-2-[[(1R)-1-(3-furanyl)-3-methylamino)propyl]oxy]-benzonitrile;

[0121]4-chloro-5-fluoro-2-[[(1R)-3-(methylamino)-1-(3-thienyl)propyl]oxy]benzonitrile;

[0122]4-chloro-5-fluoro-2-[[(1R)-3-[(2-hydroxyethyl)amino]-1-(3-thienyl)propyl]oxy]benzonitrile;

[0123]2-[[(1R)-3-[(2-aminoethyl)amino]-1-(3-thienyl)propyl]oxy]-4-chloro-5-fluoro-benzonitrile;

[0124]2-[[(1R)-3-amino-1-(3-thienyl)propyl]oxy]-4-chloro-5-fluorobenzonitrile;

[0125] 4-chloro-2-[3-(methylamino)-1-(2-thiazolyl)propoxy]-benzonitrile;

[0126]2-[[(1R)-3-amino-1-(2-thiazolyl)propyl]oxy]-4-chloro-5-fluoro-benzonitrile;

[0127] γ-(2-chloro-5-nitrophenoxy)-N-methylbenzenepropanamine;

[0128] (R)-γ-(5-chloro-2-nitrophenoxy)-N-methylbenzene)propanamine;

[0129]4-chloro-5-fluoro-2-{[(1R)-3-[(2-fluoroethyl)amino]-1-phenylpropyl]oxy}benzonitrile;

[0130]2-[[(1R)-3-amino-1-phenylpropyl]oxy]-4-bromo-5-fluorobenzonitrile;

[0131] 3-[[(3R)-3-(2,5dichlorophenoxy)-3-phenylpropyl]amino]-1-propanol;

[0132]1-[(3R)-3-(2,5-dichlorophenoxy)-3-phenylpropyl]-4-piperidinemethanol;

[0133]N-[(3R)-3-(2,5-dichlorophenoxy)-3-phenylpropyl]-2-thiophenemethanamine;

[0134]N-[(3R)-3-(2,5-dichlorophenoxy)-3-phenylpropyl]-5-methyl-2-furanmethanamine;

[0135]4-chloro-2-[[(1R)-1-phenyl-3-(1-piperazinyl)propyl]oxy]benzonitrile;

[0136]5-fluoro-2-[[(1R)-3-[(2-hydroxyethyl)amino]-1-(3-isoxazolyl)propyl]oxy]-4-methyl-benzonitrile;

[0137]2-[[(1R)-3-amnino-1-(3-isoxazolyl)propyl]oxy]-5-fluoro-4-methyl-benzonitrile;

[0138]4-chloro-2-[[(1R)-3-[(1,1-dimethylethyl)amino]-1-(3-isoxazolyl)propyl]oxy]benzonitrile;

[0139]2-[[(1R)-3-amino-1-(3-isoxazolyl)propyl]oxy]-4-chloro-benzonitrile;

[0140]2-[[(1R)-3-amino-1-(3-isoxazolyl)propyl]oxy]-4-chloro-5-fluoro-benzonitrile;

[0141] (R)-γ-(2,5-dichlorophenoxy)-3-isoxazolepropanamine;

[0142]2-[[(1R)-3-amino-1-(3-isoxazolyl)propyl]oxy]-4-(trifluoromethyl)-benzonitrile;

[0143](R)-γ-[2-chloro-5-(trifluoromethyl)phenoxy]-2-pyridinepropanamine;

[0144]2-[[(1R)-3-amino-1-(5-methyl-3-isoxazolyl)propyl]oxy]-4-chloro-5-fluoro-benzonitrile.

[0145] Unless otherwise indicated, the term “C1 to 4 alkyl” referred toherein denotes a straight or branched chain alkyl group having from 1 to4 carbon atoms. Examples of such groups include methyl, ethyl, n-propyl,i-propyl, n-butyl, i-butyl and t-butyl.

[0146] The term “C1 to 6 alkyl” is to be interpreted analogously.

[0147] Unless otherwise indicated, the term “C3 to 6 cycloalkyl”referred to herein denotes a cycloalkyl group having from 3 to 6 carbonatoms. Examples of such groups include cyclopropyl, cyclopentyl andcyclohexyl.

[0148] Unless otherwise indicated, the term “C1 to 4 alkoxy” referred toherein denotes a straight or branched chain alkoxy group having from 1to 4 carbon atoms. Examples of such groups include methoxy, ethoxy,n-propoxy, i-propoxy and t-butoxy.

[0149] Examples of a “C1 to 4 alkyl or C1 to 4 alkoxy optionally furthersubstituted by one or more fluorine atoms” include CF₃, CF₃CF₂, CF₃CH₂,CH₂FCH₂, CH₃CF₂, CF₃CH₂CH₂, OCF₃ and OCH₂CF₃.

[0150] Unless otherwise indicated, the term “halogen” referred to hereindenotes fluoro, chloro, bromo and iodo.

[0151] Examples of a 4 to 8 membered saturated azacyclic ring optionallyincorporating one further heteroatom selected from O, S or N includepyrrolidine, piperidine, piperazine, morpholine and perhydroazepine.

[0152] Examples of a five or six membered aromatic heterocyclic ringcontaining 1 to 3 heteroatoms independently selected from O, S and Ninclude fuiran, thiophene, pyridine, thiazole, imidazole, oxazole,triazole, oxadiazole, thiadiazole and pyrimidine.

[0153] Examples of a five or six membered saturated heterocyclic ringcontaining 1 to 3 heteroatoms independently selected from O, S and Ninclude pyrrolidine, tetrahydrofuran, piperidine and piperazine.

[0154] Examples of a five membered aromatic azacyclic ring optionallyincorporating one further N atom include pyrrole and imidazole.

[0155] Certain compounds of formula (I) are novel. Therefore a furtheraspect of the invention provides a compound of formula (Ia)

[0156] wherein

[0157] X and Y independently represent C1 to 4 alkyl, C1 to 4 alkoxy,halogen, CF₃, OCF₃, CN, C≡CH, S(O)_(m)CH₃, S(O)_(p)CF₃, NO₂ or NHCHO;

[0158] m and p independently represent an integer 0, 1 or 2;

[0159] Z represents H or fluoro;

[0160] V represents O;

[0161] W represents phenyl or a five or six membered aromaticheterocyclic ring containing 1 to 3 heteroatoms independently selectedfrom O, S and N; said phenyl or aromatic heterocyclic ring beingoptionally substituted by one or more substituents selectedindependently from halogen, C1 to 4 alkyl, C1 to 4 alkoxy, OH, CN, NO₂or NR⁴R⁵; said alkyl or alkoxy group being optionally furthersubstituted by one or more fluorine atoms;

[0162] R¹ and R² independently represent H, C1 to 4 alkyl or C3 to 6cycloalkyl; said alkyl group being optionally substituted by C1 to 4alkoxy, halogen, hydroxy, NR⁶R⁷, phenyl or a five or six memberedaromatic or saturated heterocyclic ring containing 1 to 3 heteroatomsindependently selected from O, S and N; said phenyl or aromaticheterocyclic ring being optionally furter substituted by halogen, C1 to4 alkyl, C1 to 4 alkoxy, CF₃, OCF₃, CN or NO₂;

[0163] or the group NR¹R² together represents a 4 to 8 memberedsaturated azacyclic ring optionally incorporating one further heteroatomselected from O, S or NR⁸; said ring being substituted by OH or by C1 to4 alkyl substituted by C1 to 4 alkoxy, OH or NR⁹R¹⁰;

[0164] or the group NR¹R² together represents part of a five memberedaromatic azacyclic ring optionally incorporating one turther N atom;

[0165] R⁴, R⁵R⁶, R⁷, R⁹ and R¹⁰ independently represent H or C1 to 4alkyl;

[0166] R⁸ represents H or C1 to 6 alkyl; said alkyl group beingoptionally substituted by C1 to 4 alkoxy, OH, NR¹¹R¹², phenyl or a fiveor six membered aromatic or saturated heterocyclic ring containing 1 to3 heteroatoms independently selected from O, S and N; said phenyl oraromatic heterocyclic ring being optionally further substituted byhalogen, C1 to 4 alkyl, C1 to 4 alkoxy, CF₃, OCF₃, CN or NO₂;

[0167] R¹¹ and R¹² independently represent H or C1 to 4alkyl;

[0168] or a pharmaceutically acceptable salt, enantiomer or racematethereof,

[0169] with the proviso that when W represents optionally substitutedphenyl, thienyl, furanyl or pyrrolyl and R¹ represents H, C1 to 4 alkylor C3 to 6 cycloalkyl optionally substituted by C1 to 4 alkoxy, then R²does not represent H, C1 to 4 alkyl or C3 to 6 cycloalkyl optionallysubstituted by C1 to 4 alkoxy; and

[0170] with the proviso that when W represents thiazolyl or pyridyl,then either Z represents F; or at least one of X and Y represents CN; orR¹ and R² do not independently represent H or CH₃.

[0171] In another aspect, the invention concerns compounds of formula(Ia), wherein X, Y, V, W, Z, R¹ and R² are as defined above, with theproviso that when R¹ is H, then R² is not H, C1 to 4 alkyl or benzyl;and with the proviso that when R¹ represents C1 to 4 alkyl or C3 to 6cycloalkyl optionally substituted by C1 to 4 alkoxy, then R² does notrepresent C1 to 4 alkyl or C3 to 6 cycloalkyl optionally substituted byC1 to 4 alkoxy.

[0172] In one preferred embodiment, X and Y in formula (1a)independently represent Br, Cl, CH₃, CF₃ or CN. It is particularlypreferred that X represents Br, Cl or CF₃. It is also particularlypreferred that Y represents Cl or CN.

[0173] Preferably, W in formula (Ia) represents an optionallysubstituted five or six membered aromatic heterocyclic ring containing 1to 3 heteroatoms independently selected from O, S and N. Particularexamples are those wherein W represents thienyl, furyl, pyridyl,thiazolyl, oxazolyl, isoxazolyl or pyrimidyl.

[0174] Preferably, R¹ and R² in formula (Ia) independently represent Hor C1 to 4 alkyl optionally substituted by C1 to 4 alkoxy or hydroxy.More preferably, R¹ and R² independently represent H or methyl.

[0175] Particular compounds of formula (Ia) include:

[0176]2-[[(3R)-3-(2,5-dichlorophenoxy)-3-(2-thienyl)propyl]amino]ethanol;

[0177]4-chloro-2-{[(1R)-3-(4-hydroxy-1-piperidinyl)-1-phenylpropyl]oxy}-benzonitrile;

[0178]4-chloro-2-{[(1R)-3-[(2-hydroxyethyl)methylamino]-1-phenylpropyl]oxy}-benzonitrile;

[0179]4-chloro-2-{[(1R)-3-[(3R)-3-hydroxypyrrolidinyl]-1-phenylpropyl]oxy}-benzonitrile;

[0180]4-chloro-2-{[(1R)-3-[(3S)-3-hydroxypyrrolidinyl]-1-phenylpropyl]oxy}-benzonitrile;

[0181]4-chloro-5-fluoro-2-[3-(methylamino)-1-(2-pyrimidinyl)propoxy]benzonitrile;

[0182]4-chloro-5-fluoro-2-({(1R)-3-[(3hydroxypropyl)amino]-1-phenylpropyl}oxy)benzonitrile;

[0183]4-chloro-5-fluoro-2-{[(1R)-1-(3-furanyl)-3-(3-hydroxypropyl)amino]propyl]oxy}benzonitrile;

[0184]4-chloro-5-fluoro-2-{[(1R)-3-[(3-hydroxypropyl)amino]-1-(3-thienyl)propyl]oxy}benzonitrile;

[0185]4-bromo-5-fluoro-2-({(1R)-3-[(3-hydroxypropyl)amino]-1-phenylpropyl}oxy)benzonitrile;

[0186]4-bromo-5-fluoro-2-({(1R)-1-(3-furanyl)-3-[(3-hydroxypropyl)amino]propyl}oxy)benzonitrile;

[0187]4-bromo-5-fluoro-2-{[(1R)-3-[(3-hydroxypropyl)amino]-1-(3-thienyl)propyl]oxy}benzonitrile;

[0188]4-chloro-5-fluoro-2-[[(1R)-3-[[(5-methylpyrazinyl)methyl]amino]-1-phenylpropyl]oxy]benzonitrile;

[0189]4-chloro-5-fluoro-2-[[(1R)-3-[(1H-imidazol-2-ylmethyl)amino]-1-phenylpropyl]oxy]benzonitrile;

[0190]4-chloro-2-[[(1R)-3-[[2-(dimethylamino)ethyl]amino]-1-phenylpropyl]oxy]-5-fluorobenzonitrile;

[0191]4-chloro-5-fluoro-2-[[(1R)-3-[[2-(4-morpholinyl)ethyl]amino]-1-phenylpropyl]oxy]benzonitrile;

[0192]4-chloro-5-fluoro-2-[[(1R)-3-[[2-(1H-imidazol-1-yl)ethyl]amino]-1-phenylpropyl]oxy]benzonitrile;

[0193]4-chloro-5-fluoro-2-[[(1R)-3-[[2-(1H-imidazol-4-yl)ethyl]amino]-1-phenylpropyl]oxy]benzonitrile

[0194]4-chloro-5-fluoro-2-[[(1R)-3-[(2-hydroxyethyl)amino]-1-phenylpropyl]oxy]benzonitrile;

[0195]2-[[(1R)-3-[(2-aminoethyl)amino]-1-phenylpropyl]oxy]-4-chloro-5-fluorobenzonitrile;

[0196]4-chloro-5-fluoro-2-[[(1R)-1-phenyl-3-[(3,3,3-trifluoropropyl)amino]propyl]oxy]benzonitrile;

[0197] 2-{[(1R)-3-amino-1-(2-thiazolyl)propyl]oxy}-4-chlorobenzonitrile;

[0198]4-chloro-2-{[(1R)-3-(methylamino)-1-(2-thiazolyl)propyl]oxy}benzonitrile;

[0199] 2-[3-amino-1-(2-oxazolyl)propoxy]-4-chlorobenzonitrile;

[0200] γ-(2,5-dichlorophenoxy)-2-oxazolepropanamine;

[0201]2-[[-3-amino-1-(3-pyridinyl)propyl]oxy]-4-chloro-5-fluorobenzonitrile;

[0202]4-chloro-5-fluoro-2-[3-(methylamino)-1-(3-pyridinyl)propoxy]benzonitrile;

[0203]2-[3-amino-1-(6-methoxy-2-pyridinyl)propoxy]-4-chloro-5-fluorobenzonitrile;

[0204]2-[3-amino-1-(1,6-dihydro-6-oxo-2-pyridinyl)propoxy]-4-chloro-5-fluorobenzonitrile;

[0205] 2-[3-amino-1-(6-bromo-3-pyridinyl)propoxy]-4-chlorobenzonitrile;

[0206] 2-[[3-amino-1-(5-isoxazolyl)propyl]oxy]-4-chlorobenzonitrile;

[0207]4-chloro-2-[3-[(2-hydroxyethyl)amino]-1-(5-isoxazolyl)propoxy]benzonitrile;

[0208] (R)-γ-(2,5-dichlorophenoxy)-5-isoxazolepropanamine;

[0209]4-chloro-5-fluoro-2-[[(1R)-3-[(2-hydroxyethyl)amino]-1-(3-thienyl)propyl]oxy]benzonitrile;

[0210]2-[[(1R)-3-[(2-aminoethyl)amino]-1-(3-thienyl)propyl]oxy]-4-chloro-5-fluoro-benzonitrile;

[0211] 4-chloro-2-[3-(methylamino)-1-(2-thiazolyl)propoxy]-benzonitrile;

[0212]2-[[(1R)-3-amino-1-(2-thiazolyl)propyl]oxy]-4-chloro-5-fluoro-benzonitrile;

[0213]4-chloro-5-fluoro-2-{[(1R)-3-[(2-fluoroethyl)amino]-1-phenylpropyl]oxy}benzonitrile;

[0214]3-[[(3R)-3-(2,5-dichlorophenoxy)-3-phenylpropyl]amino]-1-propanol;

[0215]1-[(3R)-3-(2,5-dichlorophenoxy)-3-phenylpropyl]-4-piperidinemethanol;

[0216]N-[(3R)-3-(2,5-dichlorophenoxy)-3-phenylpropyl]-2-thiophenemethanamine;

[0217]N-[(3R)-3-(2,5-dichlorophenoxy)-3-phenylpropyl]-5-methyl-2-furanmethanamine;

[0218]5-fluoro-2-[[(1R)-3-[(2-hydroxyethyl)amino]-1-(3-isoxazolyl)propyl]oxy]-4-methyl-benzonitrile;

[0219]2-[[(1R)-3-amino-1-(3-isoxazolyl)propyl]oxy]-5-fluoro-4-methyl-benzonitrile;

[0220]4-chloro-2-[[(1R)-3-[(1,1-dimethylethyl)amino]-1-(3-isoxazolyl)propyl]oxy]benzonitrile;

[0221]2-[[(1R)-3-amino-1-(3-isoxazolyl)propyl]oxy]-4-chloro-benzonitrile;

[0222]2-[[(1R)-3-amino-1-(3-isoxazolyl)propyl]oxy]-4-chloro-5-fluoro-benzonitrile;

[0223] (R)-γ-(2,5-dichlorophenoxy)-3-isoxazolepropanamine;

[0224]2-[[(1R)-3-amino-1-(3-isoxazolyl)propyl]oxy]-4-(trifluoromethyl)-benzonitrile;

[0225]2-[[(1R)-3-amino-1-(5-methyl-3-isoxazolyl)propyl]oxy]-4-chloro-5-fluoro-benzonitrile;

[0226] and pharmaceutically acceptable salts, enantiomers or racernatesthereof.

[0227] According to the invention there is also provided a compound offormula (Ia), or a pharmaceutically acceptable salt, enantiomer orracemate thereof, for use as a medicament.

[0228] According to the invention, we further provide a process for thepreparation of compounds of formula (Ia), or a pharmaceuticallyacceptable salt, enantiomer or racemate thereof which comprises:

[0229] (a) reaction of a compound of formula (II)

[0230] wherein X, Y, V and Z are as defined in formula (Ia),

[0231] with a compound of formula (III)

[0232] wherein W, R¹ and R² are as defined in formula (Ia); or

[0233] (b) reaction of a compound of formula (IV)

[0234] wherein X, Y and Z are as defined in formula (Ia) and L¹represents a leaving group,

[0235] with a compound of formula (V)

[0236] wherein R¹, R², V and W are as defined in formula (Ia); or

[0237] (c) reaction of a compound of formula (VI)

[0238] wherein X, Y, V, W and Z are as defined in formula (Ia) and L² isa leaving group,

[0239] with a compound of formula (VII)

HNR¹R²   (VII)

[0240] wherein R¹ and R² are as defined in formula (Ia); or

[0241] (d) reaction of a compound of formula (II)

[0242] wherein X, Y, V and Z are as defined in formula (Ia),

[0243] with a compound of formula (VIII)

[0244] wherein R¹, R² and W are as defined in formula (Ia) and L³ is aleaving group; or

[0245] (e) reduction of a compound of formula (IX)

[0246] wherein X, Y, V, W and Z are as defined in formula (Ia) and Grepresents a group that upon reduction is converted into a group NR¹R²;

[0247] and where necessary converting the resultant compound of formula(Ia), or another salt thereof, into a pharmaceutically acceptable saltthereof; or converting the resultant compound of formula (Ia) into afurther compound of formula (Ia); and where desired converting theresultant comhpound of formula (Ia) into an optical isomer thereof.

[0248] In process (a), the reactants (II) and (III) are coupled togetherin a suitable inert solvent such as tetrahydrofuran using, for example,Mitsunobu conditions. Thus, for example, the reactants are treated witha phosphine derivative and an azo derivative at a suitable temperature,generally between 0° C. and the boiling point of the solvent. Suitablephosphine derivatives include triphenylphosphine and tributylphosphine.Suitable azo derivatives include diethyl azodicarboxylate, diisopropylazodicarboxylate and 1,1′-(azodicarbonyl)dipiperidine.

[0249] In process (b), the reaction is performed by treating anucleophile of formula (V) with an electrophile of formula (IV) in aninert solvent. Suitable leaving groups L¹ include halides, particularlyfluoride. The reaction is generally performed in the presence of anon-nucleophilic base such as sodium hydride. Suitable organic solventsare those such as N-methyl-2-pyrrolidinone, tetrahydrofuran, C1 to 4alcohols and dimethylsulfoxide. The reaction is generally conducted at atemperature between 0° C. and the boiling point of the solvent.

[0250] Alternatively, in process (b), the reaction will take place usingan appropriate palladium source such as palladium (II) acetate in thepresence of a suitable phosphine ligand such as BINAP.

[0251] In process (c), the amination reaction is performed by reacting acompound of formula (VI) with an amine (VII) in an inert solvent.Suitable leaving groups L² include sulfonate, trifluorosulfonate,tosylate and halides selected from the group chloride, bromide oriodide. The nucleophile can be a primary or secondary amine in thepresence of a base. This base can be either an excess of the aminenucleophile or can be an additive to the reaction mixture. Potentialbasic additives are metal carbonate, especially alkali metal carbonates,metal oxides and hydroxides, and tertiary amine bases. Suitable organicsolvents are those such as acetonitrile, dioxan, N,N-dimethylformamide,N-methyl-2-pyrrolidinone, tetrahydrofuran, dimethylsulfoxide, sulfolaneand C1 to 4 alcohols.

[0252] In process (d), the reaction is performed by treating anucleophile of formula (II) with an electrophile of formula (VIII) in aninert solvent. Suitable leaving groups L³ include halides, particularlychloride or bromide. The reaction is generally performed in the presenceof a non-nucleophilic base such as sodium hydride. Suitable organicsolvents are those such as N-methyl-2-pyrrolidinone, tetrahydroflran, C1to 4 alcohols and dimethylsulfoxide. The reaction is generally conductedat a temperature between 0° C. and the boiling point of the solvent.

[0253] In process (e), G preferably represents an azido (N₃) group. Therequired reduction may then be achieved by treating a compound offormula (IX) with a suitable reducing agent such as Sn(II) ortriphenylphosphine. Preferably the reducing agent is triphenylphosphineand the reduction is carried out in a suitable inert solvent such astetrahydrofuran.

[0254] It will be apparent to a person skilled in the art that in theabove processes it may be desirable or necessary to protect an amine,hydroxyl or other potentially reactive group.

[0255] Suitable protecting groups and details of processes for addingand removing such groups may be found by reference to the standard text“Protecting Groups in Organic Synthesis”, 2nd Edition (1991) by Greeneand Wuts. In one preferred embodiment, amine groups are protected ascarbamate derivatives, for example, as t-butyloxycarbamates. Thus,compounds of formula (Ia) in which R¹ is H are conveniently prepared byremoval of a carbamate protecting group from a corresponding compound offormula (Ia) wherein R¹ is a carbamate group, especially at-butyloxycarbamate group. Removal of the carbamate group isconveniently effected using hydrogen chloride in dioxan.

[0256] The present invention includes compounds of formula (Ia) in theform of salts, in particular acid addition salts. Suitable salts includethose formed with both organic and inorganic acids. Such acid additionsalts will normally be pharmaceutically acceptable although salts ofnon-pharmaceutically acceptable acids may be of utility in thepreparation and purification of the compound in question. Thus,preferred salts include those formed from hydrochloric, hydrobromic,sulphuric, phosphoric, citric, tartaric, lactic, pyruvic, acetic,succinic, fumaric, maleic, methanesulphonic and benzenesulphonic acids.

[0257] Salts of compounds of formula (Ia) may be formed by reacting thefree base, or a salt, enantiomer or racemate thereof, with one or moreequivalents of the appropriate acid. The reaction may be carried out ina solvent or medium in which the salt is insoluble or in a solvent inwhich the salt is soluble, for example, water, dioxan, ethanol,tetrahydrofuran or diethyl ether, or a mixture of solvents, which may beremoved in vacuo or by freeze drying. The reaction may also be ametathetical process or it may be carried out on an ion exchange resin.

[0258] Certain novel intermediates of formulae (III), (V), (VI), (VIII)and (IX) form another aspect of the invention.

[0259] Compounds of formula (III) may be prepared by reaction of acompound of formula (IX)

[0260] wherein R¹ and R² are as defined in formula (Ia),

[0261] with an organometallic derivative, W-M, wherein W is as definedin formula (Ia) and M represents a metallic residue such as lithium ormagnesium-halide.

[0262] Compounds of formula (IX) may be prepared by:

[0263] (a) reacting a compound of formula (II), as defined above, with acompound of formula (XI)

[0264] wherein W and G are as defined above; or

[0265] (b) reacting a compound of formula (IV), as defined above, with acompound of formula (XII)

[0266] wherein V, W and G are as defined above.

[0267] Compounds of formulae (II), (IV), (VII), (X), (XI) and (XII) areeither known or may be prepared using known methods. Some such methodsare illustrated within the Examples that are included herein. Othersuitable methods will be readily apparent to the man skilled in the art.

[0268] Intermediate compounds may be used as such or in protected form.Protecting groups and details of processes for their removal may befound by reference to the standard text “Protecting groups in OrganicSynthesis”, 2nd Edition (1991) by Greene and Wuts.

[0269] The compounds of the invention and intermediates thereto may beisolated from their reaction mixtures and, if necessary furtherpurified, by using standard techniques.

[0270] The compounds of formula (Ia) may exist in enantiomeric forms.Therefore, all enantiomers, diastereomers, racemates and mixturesthereof are included within the scope of the invention. The variousoptical isomers may be isolated by separation of a racemic mixture ofthe compounds using conventional techniques, for example, fractionalcrystallisation, or HPLC.

[0271] Intermediate compounds may also exist in enantiomeric forms andmay be used as purified enantiomers, diastereomers, racemates ormixtures.

[0272] The compounds of formula (Ia), and their pharmaceuticallyacceptable salts, enantiomers and racemates, are useful because theypossess pharmacological activity in animals. In particular, thecompounds of formulae (I) and (Ia) are active as inhibitors of theenzyme nitric oxide synthase. More particularly, they are inhibitors ofthe inducible isoform of the enzyme nitric oxide synthase and as suchare predicted to be useful in therapy, for example, asanti-inflanmmatory agents. They may also have utility as inlibitors ofthe neuronal isoform of the enzyme nitric oxide synthase.

[0273] The compounds of formulae (I) and (Ia) and their pharmaceuticallyacceptable salts, enantiomers and racemates are indicated for use in thetreatment or prophylaxis of diseases or conditions in which synthesis oroversynthesis of nitric oxide synthase forms a contributory part. Inparticular, the compounds are indicated for use in the treatment ofinflammatory conditions in mamnmals including man.

[0274] Conditions that may be specifically mentioned are:

[0275] osteoarhritis, rheumatoid arthritis, rheumatoid spondylitis,gouty arthritis and other arthritic conditions, inflamed joints;

[0276] eczema, psoriasis, dermatitis or other inflammatory skinconditions such as sunburn;

[0277] inflammatory eye conditions including uveitis, glaucoma andconjunctivitis;

[0278] lung disorders in which inflammation is involved, for example,asthma, bronchitis, chronic obstructive pulmonary disease, pigeonfancier's disease, farmer's lung, acute respiratory distress syndrome;

[0279] bacteraemia, endotoxaemia (septic shock), aphthous ulcers,gingivitis, pyresis, pain, meningitis and pancreatitis;

[0280] conditions of the gastrointestinal tract including inflammatorybowel disease, Crohn's disease, atrophic gastritis, gastritisvarialoforme, ulcerative colitis, coeliac disease, regional ileitis,peptic ulceration, irritable bowel syndrome, reflux oesophagitis, damageto the gastrointestinal tract resulting from infections by, for example,Helicobacter pylori, or from treatments with non-steroidalanti-inflammatory drugs;

[0281] and other conditions associated with inflammation.

[0282] By virtue of their pharmacological activity as inhibitors of theenzyme nitric oxide synthase, the compounds will also be useful in thetreatment and alleviation of acute pain or persistent inflammatory painor neuropathic pain or pain of a central origin.

[0283] We are particularly interested in the conditions inflammatorybowel disease, rheumatoid arthritis, osteoarthritis, chronic obstructivepulmonary disease and pain.

[0284] The compounds of formulae (I) and (Ia) and their pharmaceuticallyacceptable salts, enantiomers and racernates may also be useful in thetreatment or prophylaxis of diseases or conditions in addition to thosementioned above. For example, the compounds may be useful in thetreatment of atherosclerosis, cystic fibrosis, hypotension associatedwith septic and/or toxic shock, in the treatment of dysfunction of theimmune system, as an adjuvant to short-term immunosuppression in organtransplant therapy, in the control of onset of diabetes, in themaintenance of pancreatic function in diabetes, in the treatment ofvascular complications associated with diabetes and in co-therapy withcytokines, for example TNF or interleukins.

[0285] The compounds of formulae (I) and (Ia) may also be useful in thetreatment of hypoxia, for example in cases of cardiac arrest and stroke,neurodegenerative disorders including nerve degeneration and/or nervenecrosis in disorders such as ischaeria, hypoxia, hypoglycaemia,epilepsy, and in external wounds (such as spinal cord and head injury),hyperbaric oxygen convulsions and toxicity, dementia, for examplepre-senile dementia, Alzheimer's disease and AIDS-related dementia,Sydenham's chorea, Parkinson's disease, Tourette's Syndrome,Huntington's disease, Amyotrophic Lateral Sclerosis, Multiple Sclerosis,Korsakoff's disease, imbecility relating to a cerebral vessel disorder,sleeping disorders, schizophrenia, autism, seasonal affective disorder,jet-lag and septic shock. Compounds of formulae (I) and (Ia) may also beexpected to show activity in the prevention and reversal of drugaddiction or tolerance such as tolerance to opiates and diazepines,treatment of migraine and other vascular headaches, neurogenicinflammation, in the treatment of gastrointestinal motility disorders,cancer and in the induction of labour.

[0286] We are particularly interested in the conditions stroke,Alzheimer's disease, Parkinson's disease, multiple sclerosis,schizophrenia, migraine, cancer and septic shock.

[0287] Prophylaxis is expected to be particularly relevant to thetreatment of persons who have suffered a previous episode of, or areotherwise considered to be at increased risk of, the disease orcondition in question. Persons at risk of developing a particulardisease or condition generally include those having a family history ofthe disease or condition, or those who have been identified by genetictesting or screening to be particularly susceptible to developing thedisease or condition.

[0288] For the above mentioned therapeutic indications, the dosageadministered will, of course, vary with the compound employed, the modeof administration and the treatment desired. However, in general,satisfactory results are obtained when the compounds are administered ata dosage of the solid form of between 1 mg and 2000 mg per day.

[0289] The compounds of formula (Ia), and pharmaceutically acceptablederivatives thereof, may be used on their own, or in the forrn ofappropriate pharmaceutical compositions in which the compound orderivative is in admixture with a pharmaceutically acceptable adjuvant,diluent or carrier. Administration may be by, but is not limited to,enteral (including oral, sublingual or rectal), intranasal, intravenous,topical or other parenteral routes. Conventional procedures for theselection and preparation of suitable pharmaceutical formulations aredescribed in, for example, “Pharmaceuticals—The Science of Dosage FormDesigns”, M. E. Aulton, Churchill Livingstone, 1988. The pharmaceuticalcomposition preferably comprises less than 80% and more preferably lessthan 50% of a compound of formula (Ia), or a pharmaceutically acceptablesalt, enantiomer or racemate thereof.

[0290] There is also provided a process for the preparation of such apharmaceutical composition which comprises mixing the ingredients.

[0291] The compounds of formulae (I) and (Ia), and pharmaceuticallyacceptable derivatives thereof, may also be advantageously used incombination with a COX-2 inhibitor. Particularly preferred COX-2inhibitors are Celecoxib and MK-966. The NOS inhibitor and the COX-2inhibitor may either be formulated together within the samepharmaceutical composition for administration in a single dosage unit,or each component may be individually formulated such that separatedosages may be administered either simultaneously or sequentially.

[0292] The invention is illustrated, but in no way limited, by thefollowing examples:

EXAMPLE 1

[0293] 2-(3-Amino-1-phenylpropoxy)-4-chlorobenzonitrile hydrochloride

[0294] a) (3-Hydroxy-3-phenylpropyl)carbamic acid 1,1-dimethylethylester

[0295] α-(2-Aminoethyl)benzenemethanol (1.21 g, 8 mmol) was dissolved indry tetrahydrofuran (50 ml) and treated with di-tert-butyl dicarbonate(1.92 g, 8.8 mmol) followed by triethylamine (1.34 ml, 9.6 mmol) and themixture stirred for 18 h. The reaction mixture was evaporated and theresidue eluted down a flash chromatography column using ether/isohexane(1:1) as eluent to give the product (974 mg, 48%) as a viscous yellowoil.

[0296]¹H NMR 300 MHz (CDCl₃) 7.35 (4H, m), 7.26 (1H, m), 4.89 (1H, brs), 4.75 (1H, m), 3.49 (1H, br m), 3.17 (2H, m), 1.86 (2H, m), 1.45 (9H,s).

[0297] b) 2-(3-Amino-1-phenylpronoxy)-4-chlorobenzonitrile hydrochloride

[0298] Triphenylphosphine (67 mg, 2.56 mmol) was dissolved in toluene(50 ml) and the solution cooled to 0° C. Diethyl diazodicarboxylate (45mg, 2.56 mmol) was added dropwise and the solution stirred for 20 min.4-Chloro-2-hydroxybenzonitrile (36 mg, 2.34 mmol) in toluene (25 ml) andtetrahydrofuran (10 ml) was added dropwise followed by(3-hydroxy-3-phenylpropyl)carbamic acid 1,1-dimethylethyl ester (59 mg,2.34 mmol) in toluene (25 ml). The reaction mixture was allowed to warmto room temperature over the weekend, evaporated, and the residue eluteddown a flash chromatography column using 10% ether/isohexane as eluentto give the required product protected as the t-butyl carbamate. Thismaterial was stirred with 4M hydrogen chloride in dioxan (8 ml) for 2 h,the solvent evaporated, and the residue triturated with dry ether togive the title compound (64 mg, 8.5%) as a colourless solid.

[0299] MS APCI+ve^(m)/z 287 ([M+H)⁺).

[0300]¹H NMR 300 MHz (d₆-DMSO) 8.02 (3H, br s), 7.79 (1H, d), 7.44−7.29(5H, m), 7.22 (1H, d), 7.16 (1H, d of d), 5.88 (1H, m), 2.93 (2H, br m),2.32 (1H, m), 2.19 (1H, m).

EXAMPLE 2

[0301] 4-Chloro-2-(3-(methylamino)-1-phenylpropoxy)benzonitrilehydrochloride

[0302] a) 3-Hydroxy-3-phenylpropyl)methylcarbamic acid 1,1-dimethylethylester

[0303] [2-(Methylamino)ethyl]benzenemethanol (10.8 g, 65.5 mmol) inmethanol (150 ml) was treated with di-tert-butyl dicarbonate (14.7 g,67.4 mmol) followed by triethylamine (19.0 ml, 136 mmol) and thereaction mixture stirred for 4 h. The solvent was evaporated and theresidue eluted down a flash chromatography column using ether/isohexane(1:1) as eluent to give the required product (15.7 g, 90%) as a viscousoil.

[0304] GC/MS ^(m)/z 165 (M−100)⁺.

[0305] b) 4-Chloro-2-[3-(methylamino)-1-phenylpropoxy]benzonitrilehydrochloride

[0306] To triphenylphosphine (0.38 g, 1.46 mmol) in dry tetrahydrofuran(10 ml) under nitrogen was added diisopropyl azodicarboxylate (0.29 ml,1.46 mmol) dropwise over 2 min. with stirring. The reaction mixture wasstirred for 20 min. and then 4-chloro-2-hydroxybenzonitrile (0.22 g,1.46 mmol) in dry tetrahydrofuran (5 ml) was added, followed 5 minuteslater by 3-hydroxy-3-phenylpropyl)methylcarbamic acid 1,1-dimethylethylester (0.39 g, 1.46 mmol) in dry tetrahydrofuran (5 ml) and the reactionmixture stirred overnight. The mixture was diluted with ethyl acetate,washed with 10% aqueous sodium carbonate (2×50 ml), then brine and driedover magnesium carbonate. The solvent was evaporated and the residueeluted down a flash chromatography column initially with ether isohexane(1:1) then re-eluting the cleaner fractions with ether/isohexane (3:7)to give the amide protected product. This was stirred with 4M hydrogenchloride in dioxan (5 ml) for 1 h, evaporated, and the residuetriturated with ether to give the title compound (96 mg, 20%) as acolourless solid.

[0307] MS APCI+ve ^(m)/z 301 ([M+H]⁺).

[0308]¹H NMR 300 MHz (d₆-DMSO) 7.78 (1H, d), 8.93 (2H, br s), 7.44−7.31(5H, m), 7.27 (1H, d ), 7.16 (1H, d of d), 5.91 (1H, m), 2.98 (2H, m),2.57 (3H, s), 2.41−2.15 (2H, m).

EXAMPLE 3

[0309] 4-Bromo-2-[(1R)-3-(Methylamino)-1-phenylpropoxy]benzonitrilehydrochloride

[0310] a) [(3R)-3-Hydroxy-3-phenylpropyl]methylcarbamic acid1,1-dimethylethyl ester

[0311] Prepared as for Example 2(a), to give the required product (6.0g, 78%) as a viscous oil. MS APCI+ve ^(m)/z 166 ([M−100+H]⁺).

[0312] b) [(3R)-3-(5-Bromo-2-cyanophenoxy)-3-phenylpropyl]methylcarbamicacid 1,1-dimethyl ester.

[0313] [(3R)-3-Hydroxy-3-phenylpropyl]methylcarbamic acid1,1-dimethylethyl ester (0.4 g, 1.5 mmol) and4-bromo-2-fluorobenzonitrile (0.3 g, 1.5 mmol) were dissolved intetrahydrofuran (10 ml). 60% Sodium hydride (0.08 g, 2.0 mmol) was addedand the mixture was stirred for 4 h. The reaction mixture was thenquenched with water, extracted with ethyl acetate, dried over magnesiumsulphate, filtered and rotary evaporated. Purification by flashchromatography with 20% ethyl acetate/hexane as eluent gave the requiredproduct (0.49 g, 73%) as a colourless oil.

[0314] MS APCI+ve ^(m)/z 345/7 ([M−100+H]⁺).

[0315] c) 4-Bromo 2-[(1R)-3-(methylamino)-1-phenylpropoxy]benzonitrilehydrochloride[(3R)-3-(5-Bromo-2-cyanophenoxy)-3-phenylpropyl]methylcarbamic acid1,1-dimethyl ester (0.45 g, 1 mmol) was stirred in 4M hydrogen chloridein dioxan (10 ml) for 4 h. The solvent was evaporated and the residuetreated with ether to give the required product (0.34 g, 89%) as a whitesolid.

[0316] MS APCI+ve ^(m)/z 345/7 ([M+H]+).

[0317] MS APCI+ve ^(m)/z 345/7 ([M+H]⁺).

[0318]¹H NMR 300 MHz (d₆-DMSO) 9.03 (2H, s), 7.71 (1H, d), 7.41-7.45(5H, m) 7.36 (1H, m), 7.27 (1H, d), 5.94 (1H, m), 2.94-3.04 (2H, m),2.56 (3H, s), 2.31-2.40 (1H, m), 2.19-2.26 (1H, m).

EXAMPLE 4

[0319] γ-R-(2-Bromo-5-chlorophenoxy)-N-methylbenzenepropanaminehydrochloride

[0320] α-[2-(Methylamino)ethyl]-(α1R)-benzenemethanol (0.395 g, 2.39mmol) was dissolved in dimethylsulphoxide (3 ml) and 60% sodium hydride(0.19 g, 4.78 mmol) added. The mixture was heated at 40° C. for 30 min,1-bromo-4-chloro-2-fluorobenzene (0.5 g, 2.39 mmol) was added and themixture was stirred at 50° C. for 20 h. The mixture was cooled to roomtemperature, quenched with water, extracted with ethyl acetate, driedover magnesium sulphate, filtered and evaporated. The residue waspurified by flash chromatography with 5% 7M ammonia-methanol indichloromethane as eluent to give the required product (0.47 g, 50%) asa white solid.

[0321] MS APCI+ve ^(m)/z 354/5/6/7/8 ([M+H]⁺).

[0322]¹H NMR 300 MHz (d₆-DMSO) 9.05 (2H, s), 7.59 (1H, d), 7.39-7.42(5H, m), 7.31-7.34 (1H, m), 6.92 (1H, d), 5.82 (1H, m), 2.95-3.00 (2H,m), 2.56 (3H, s), 2.28-2.37 (1H, m), 2.19-2.25 (1H, m).

EXAMPLE 5

[0323] 4-Chloro-2-{[(1R)-3-chloro-1-phenylpropyl]oxy}benzonitrilehydrochloride

[0324] a) 4-Chloro-2-{[(1R)-3-chloro-1-phenylpropyl]oxy}benzonitrile

[0325] (S)-α-(2-Chloroethyl)benzenemethanol (170 mg, 1.0 mmol),4-chloro-2-hydroxybenzonitrile (154 mg, 1.0 mmol.) andtriphenylphosphine (260 mg, 1.0 mmol.) in dry tetrahydrofuran (5 ml)were stirred in an ice bath under nitrogen whilst diethylazodicarboxylate (0.16 ml, 1.0 mmol.) was added. The reaction mixturewas allowed to warn to room temperature and stirred for 3 days. Thesolvent was evaporated and the residue dissolved in toluene, added tothe top of a flash chromatography column and eluted with 10%ether/isohexane to give the product (220 mg, 72%) as a viscous oil.

[0326]¹H NMR 300 MHz (CDCl₃) 7.21 (1H, d), 7.24-7.33 (5H, m), 6.92 (1H,d of d), 6.75 (1H, d), 5.43 (1H, m), 3.80 (1H, m), 3.56 (1H, m), 2.50(1H, m), 2.18 (1H, m).

[0327] b) 4-Chloro-2-{[(1R)-3-iodo-1-phenylpropyl]oxy}benzonitrile

[0328] 4-Chloro-2-{[(1R)-3-chloro-1-phenylpropyl]oxy}benzonitrile(220mg, 0.718 mmol) was dissolved in acetone (20 ml) which hadpreviously been saturated with sodium iodide and the solution was heatedunder reflux for 18 h. The reaction mixture was cooled, filtered,evaporated and the residue partitioned between water and ethyl acetate.The organic layer was separated, washed twice with water and dried(magnesium sulphate). The solvent was evaporated to leave 0.24 g (84%)of the product as a yellow oil. This was used without purification forthe next step.

[0329] c)4-Chloro-2-{[1R)-3-(methylamino)-1-phenylpropyl]oxy}benzonitrilehydrochloride

[0330] 4-Chloro-2-{[(1R)-3-iodo-1-phenylpropyl]oxy}benzonitrile (240 mg,0.604 mmol.) was dissolved in tetrahydrofuran (10 ml), treated with 40%aqueous methylamine (5 ml) and stirred for 5 h at room temperature. Thesolvents were removed in vacuo and the residue dissolved in water andextracted into ethyl acetate which was dried (magnesium sulphate). Thesolvent was evaporated and the residue stirred with 4M hydrogen chloridein dioxan (5 ml) for 1 h. The solvent was evaporated and the residueazeotroped twice with ether and finally triturated with ether to givethe required product (155 mg, 76%) as a fawn coloured solid.

[0331] MS APCI+ve ^(m)/z 301 ([M+H]⁺).

[0332]¹H NMR 300 MHz (d₆-DMSO) 8.86 (2H, br s), 7.79 (1H, d), 7.44−7.31(5H, m), 7.26 (1H, d), 7.16 (1H, d of d), 5.90 (1H, m), 3.01 (2H, br m),2.57 (3H, t,) 2.41−2.15 (2H, m).

EXAMPLE 6

[0333]4-Methoxy-2-[3-(methylamino)-1-phenylamino-1-phenylpropoxy]benzonitrilehydrochloride

[0334] The title compound was prepared by the method of Example 2(b)using 2-hydroxy-4-methoxy-benzonitrile to give 0.13 g (27%) of theproduct as a glassy solid.

[0335] MS APCI+ve ^(m)/z 297 ([M+H]⁺).

[0336]¹H NMR 300 MHz (d₆-DMSO) 8.92 (2H, br s), 7.64 (1H, d), 7.46−7.30(5H, m), 6.66 (1H, d), 6.63 (1H, d of d), 5.85 (1H, m), 3.73 (3H, s),300 (2H, br m), 2.57 (3H, s), 2.37 −2.18 (2H, m).

EXAMPLE 7

[0337] 4-Methyl-2-{[(1R)-3-(methylamino)-1-phenylpropyl]oxy}benzonitrile hydrochloride

[0338] The title compound was prepared by the method of Example 1(b)using initially [(3R)-3-hydroxy-3-phenylpropyl]methylcarbamic acid1,1-dimethylethyl ester and 2-hydroxy-4-methylbenzonitrile to give 0.35g (73%) of the product as a colourless solid.

[0339] MS APCI+ve ^(m)/z 281 ([M+H]⁺).

[0340]¹H NMR 300 MHz (d₆-DMSO) 9.09 (2H, br), 7.58 (1H, d), 7.39-7.46(4H, m), 7.32 (1H, m), 7.02 (1H, s), 6.87 (1H, d), 5.84 (1H, m), 3.00(2H, m) 255 (3H, s), 2.30 -2.39 (1H, m), 2.19-2.25 (1H, m), 2.25 (3H,s).

EXAMPLE 8

[0341] R-γ-(2,5-Dichlorophenoxy)-N-methyl-2-thiophenepropanamine

[0342] a) 2-[(1R)-3-Chloro-1-(2,5-dichlorophenoxy)propyl]thiophene

[0343] A solution of diethyl azodicarboxlate (0.7 ml) was added to asolution of S-α-(2-chloroethyl)-2-thiophenemethanol (657 mg),2,5-dichlorophenol (607 mg) and triphenylphosphine (1.17 g) in toluene(10 ml) at 0° C. and the mixture was stirred at 0° C. for 3 h and at 20°C. for 14 h. The solvent was removed in vacuo and the residue purifiedby chromatography on silica eluting with petrol—diethyl ether (9:1) togive the title compound as a colourless oil (788 mg).

[0344]¹H NMR (CDCl₃) 7.32−6.84 (6H, m), 5.72−5.65 (1H, m), 3.87−3.81(1H, m), 3.68−3.60 (1H, m), 2.69−2.58 (1H, m), 2.41−2.32 (2H, m).

[0345] b) 2-[(1R)-1-(2,5-Dichlorophenoxy)-3-iodopropyl]thiophene

[0346] A solution of the product from step (a) (788 mg) and sodiumiodide (4.5 g) in acetone (30 ml) was heated under reflux for 18 h. Thesolvent was removed in vacuo, water added and the mixture was extractedtwice with ether. The organic layers were dried (magnesium sulphate),evaporated and purified by chromatography on silica eluting withpetrol—diethyl ether (19:1) to give the title compound as a pale yellowoil (742 mg).

[0347]¹H NMR (CDCl₃) 7.30−7.23 (2H, m), 7.09 (1H, d), 6.99−6.86 (3H, m),5.59−5.53 (1H, m), 3.47−3.39 (1H, m), 3.29−3.21 (1H, m), 2.72−2.60 (1H,m), 2.47−2.36 (1H, m).

[0348] c) R-γ-(2,5-Dichlorophenoxy)-N-methyl-2-thiophenepropanaminefumarate

[0349] A solution of the product from step (b) (217 mg) in 40% aqueousmethylamine (5 ml) and tetrahydrofuran (5 ml) was stirred for 2.5 days.The solvent was removed in vacuo, water added and the mixture wasextracted three times with ethyl acetate. The organic layers were dried(sodium sulphate), evaporated and purified by chromatography on silicaeluting with dichloromethane—7M ammonia in methanol (19:1) to give anoil (116 mg). To a solution of this oil in ethyl acetate was added asolution of fumaric acid (43 mg) in methanol. The precipitate wascollected and dried to give the title compound as a fine white solid(127 mg).

[0350] MS (APCI) ^(m)/z 316 [(M+H)⁺].

[0351]¹H NMR 300 MHz (d₆-DMSO) 7.53 (1H, d), 7.44 (1H, d), 7.30 (1H, s),7.21 (1H, d), 7.04−6.95 (2H, m), 6.43 (2H, s), 6.05 (1H, dd), 2.97−2.85(2H, m), 2.49 (3H, s), 2.44−2.16 (2H, m).

EXAMPLE 9

[0352] S-γ-(2,5-Dichlorophenoxy)-N-methyl-2-thiophenepropanamine

[0353] a) 2-[(1S)-3-Chloro-1-(2,5-dichlorophenoxy)propyl]thiophene

[0354] The title compound was prepared according to the method ofExample 8(a) using R-α-(2-chloroethyl)-2-thiophenemethanol.

[0355]¹H NMR 300 MHz (CDCl₃) 7.32−6.84 (6H, m), 5.72−5.65 (1H, m),3.87−3.81 (1H, m), 3.68−3.60 (1H, m), 2.69−2.58 (1H, m), 2.41−2.32 (1H,m).

[0356] b) 2-[(1S)-1-(2,5-Dichlorophenoxy)-3-iodopropyl]thiophene

[0357] The title compound was prepared according to the method ofExample 8(b) using the product from step (a).

[0358]¹H NMR 300 MHz (CDCl₃) 7.30−7.23 (2H, m), 7.09 (1H, d), 6.99−6.86(3H, m), 5.59−5.53 (1H, m), 3.47−3.39 (1H, m), 3.29−3.21 (1H, m),2.72−2.60 (1H, m), 2.47−2.36 (1H, m).

[0359] c) S-γ-(2.5-Dichlorophenoxy)-N-methyl-2-thiophenepropanaminefumarate

[0360] The title compound was prepared according to the method ofExample 8(c) using the product from step (b).

[0361] MS (APCI) ^(m)/z 316 [(M+H)⁺].

[0362]¹H NMR 300 MHz (d₆-DMSO) 7.53 (1H, d), 7.44 (1H, d), 7.30 (1H, s),7.21 (1H, d), 7.04−6.95 (2H, m), 6.43 (2H, s), 6.04-6.60 (1H, m),2.95−2.84 (2H, m), 2.48 (3H, s), 2.43−2.29 (1H, m), 223−2.13 (1H, m).

EXAMPLE 10

[0363]2-[[(3R)-3-(2,5-Dichlorophenoxy)-3-(2-thienyl)propyl]amino]ethanolfumarate

[0364] A solution of the product from Example 8(b) (214 mg) andethanolamine (0.1 ml) in tetrahydrofuran (5 ml) was stirred for 2.5days. The solvent was removed in vacuo, water added and the mixture wasextracted three times with ethyl acetate. The organic layers were dried(sodium sulphate), evaporated and purified by chromatography on silicaeluting with dichloromethane—7M ammonia in methanol (19:1) to give anoil (116 mg). To a solution of this material in ethyl acetate was addeda solution of fumaric acid (43 mg) in methanol. The precipitate wascollected and dried to give the title compound as a fine white solid(127 mg).

[0365] MS (APCI) ^(m)/z 346 [(M+H)⁺].

[0366]¹H NMR 300 MHz (d₆-DMSO) 7.51 (1H, d), 7.43 (1H, d), 7.32 (1H, s),7.20 (1H, d), 7.01−6.98 (2H, m), 6.43 (2H, s), 6.01 (1H, t), 3.53 (2H,t), 2.84−2.74 (4H, m), 2.38−2.28 (1H, m), 2.18−2.1 (1H, m).

EXAMPLE 11

[0367]4-Chloro-2-{[(1R)-3-(4-methyl-1-piperazinyl)-1-phenylpropyl]oxy}-benzonitriledihydrochloride

[0368] 4-Chloro-2-{[(1R)-3-chloro-1 phenylpropyl]oxy}-benzonitrile (0.17g), 4-methylpiperazine (0.2 g), potassium iodide (0.02 g) inN-methylpyrrolidone (5 ml) were heated at 100° C. for 3 h. The reactionmixture was allowed to cool to ambient temperature and poured into waterand the product extracted into ethyl acetate. The ethyl acetate solutionwas washed with water, brine, dried over magnesium sulphate andevaporated to dryness to afford an oil. The oil was triturated with I Mhydrogen chloride in ether to afford the product as the dihydrochloridesalt (0.135 g).

[0369] MS APCI+ve ^(m)/z 370 [(M+H)⁺].

[0370]¹H NMR (d₆-DMSO) 7.78 (1H, dd), 7.33-7.48 (5H, m), 7.29 (1H, s),7.16 (1H, dd), 5.89 (1H, m), 3.2-4.8 (10H, m), 2.82 (3H, s), 2.45-2.50(2H, m).

EXAMPLE 12

[0371]4-Chloro-2-{[(1R)-3-(4-hydroxy-1-piperidinyl)-1-phenylpropyl]oxy}-benzonitrilefumarate

[0372] 4-Chloro-2-{[(1R)-3-chloro-1-phenylpropyl]oxy}-benzonitrile and4-hydroxy-piperidine were reacted as described in Example 11 to affordthe title compound. This was converted into the fumarate salt bytrituration with one equivalent of fumaric acid in methanol.

[0373] MS APCI+ve ^(m)/z 371 [(M+H)⁺].

[0374]¹H NMR (d₆-DMSO) 7.51 (1H, d), 7.26-7.38 (5H, m), 6.97 (1H, d),6.9 (1H, s), 6.70 (2H, s), 5.50 (1H, m), 3.65-3.75 (1H, m), 2.85-2.95(2H, m), 2.6-2.82 (2H, m), 2.35-2.50 (2H, m), 2.2-2.3 (1H, m), 2.05−2.01(1H, m), 1.86-2.0 (2H, m), 1.6-1.7 (2H, m).

EXAMPLE 13

[0375]4-Chloro-2-{[(1R)-3-[(2-hydroxyethyl)methylamino]-1-phenylpropyl]oxy}-benzonitrilehydrochloride

[0376] 4-Chloro-2-{[(1R)-3-chloro-1-phenylpropyl]oxy}-benzonitrile and(2-methylamino)-ethanol were reacted as described in Example 11 toafford the title compound.

[0377] MS APCI+ve ^(m)/z 345 [(M+H)⁺].

[0378]¹H NMR (CDCl₃) 7.48 (1H, d), 7.31-7.45 (5H, m), 7.00 (1H, dd),6.88 (1H, d), 5.66 (1H, dd), 5.01 (1H, bs), 4.00 (2H, m), 3.27 (1H, bs),2.92 (3H, s), 2.53-2.60 (6H, m).

EXAMPLE 14

[0379]4-Chloro-2-{[(1R)-3-(4-morpholinyl)-1-phenylpropyl]oxy}-benzonitrilefumarate

[0380] 4-Chloro-2-{[(1R)-3-chloro-1-phenylpropyl]oxy}-benzonitrile andmorpholine were reacted as described in Example 11 to afford the titlecompound. This was converted into the fumarate salt by trituration withone equivalent of fumaric acid in methanol.

[0381] MS APCI+ve ^(m)/z 357 [(M+H)⁺].

[0382]¹H NMR (d₆-DMSO) 7.49 (1H, dd), 7.29-7.38 (5H, m), 7.29 (1H, dd),6.92 (1H, d), 6.76 (2H, s), 5.42 (1H, m), 3.71 (4H, m), 2.5-2.7 (2H, m),2.43-2.49 (4H, m), 2.24-2.31 (1H, m), 2.02-2.22 (1H, m).

EXAMPLE 15

[0383]4-Chloro-2-{[(1R)-3-[(3R)-3-hydroxypyrrolidinyl]-1-phenylpropyl]oxy}-benzonitrilefumarate

[0384] 4-Chloro-2-{[(1R)-3-chloro-1-phenylpropyl]oxy}-benzonitrile and(3R)-3-hydroxypyrrolidine were reacted as described in Example 11 toafford the title compound. This was converted into the fumarate salt bytrituration with one equivalent of fumaric acid in methanol.

[0385] MS APCI+ve ^(m)/z 357/359 [(M+H)⁺].

[0386]¹H NMR (d₆-DMSO) 7.76 (1H, d), 7.25-7.45 (5H, m), 7.20 (1H, s),7.10 (1H, dd), 6.55 (2H, s) 5.75 (1H, m), 4.24 (1H, m), 2.95 (1H, m),2.91 (1H, m), 2.82 (2H, m), 2.51 (2H, m) 2.18-2.3 (1H, m), 1.97-2.05(2H, m), 1.62-1.64 (1H, m).

EXAMPLE 16

[0387]4-Chloro-2-{[(1R)-3-[(3S)-3-hydroxypyrrolidinyl]-1-phenylpropyl]oxy}-benzonitrilefumarate

[0388] 4-Chloro-2-{[(1R)-3-chloro-1-phenylpropyl]oxy}-benzonitrile and(3S)-3-hydroxypyrrolidine were reacted as described in Example 11 toafford the title compound. This was converted into the fumarate salt bytrituration with one equivalent of fumaric acid in methanol.

[0389] MS APCI+ve ^(m)/z 357/359 [(M+H)⁺].

[0390]¹H NMR (d₆-DMSO) 7.76 (1H, d), 7.25-7.45 (5H, m), 7.20 (1H, s),7.10 (1H, dd), 6.55 (2H, s) 5.75 (1H, m), 4.24 (1H, m), 2.95 (1H, m),2.91 (1H, m), 2.82 (2H, m), 2.51 (2H, m), 2.18-2.3 (1H, m), 1.97-2.05(2H, m), 1.62-1.64 (1H, m).

EXAMPLE 17

[0391]2-{[(1R)-3-Amino-1-phenylpropyl]oxy}-5-fluoro-4-methylbenzonitrileFumarate

[0392] a) 5-Fluoro-2-hydroxy-4-methylbenzonitrile

[0393] To a IM solution of boron trichloride in dichloromethane (48 ml,48 mmol) was added, in sequence, a solution of 4-fluoro-3-methylphenol(4.44 ml, 40 mmol) in dichloromethane (40 ml), methyl thiocyanate (3.3ml, 48 mmol) and anhydrous aluminium chloride (5.4 g, 40 mmol) at 0° C.with stirring. The reaction mixture was heated under reflux for 3 h, andstirred at room temperature overnight. The solvent was evaporated,replaced by dichloroethane and added to ice and 4N sodium hydroxide (132ml). The mixture was heated at reflux for 0.5 h with stirring, cooled toroom temperature, the organic layer separated, and the aqueous layerfurther washed with dichloroethane. The aqueous layer was acidified with2M hydrochloric acid and the solid that had precipitated collected byfiltration, and washed well with water. The solid was dissolved in ethylacetate, dried over magnesium sulphate, evaporated and the residuetriturated with isohexane with ice cooling to give 3.5 g (58%) of thesub title compound as a colourless solid.

[0394]¹H NMR 300 MHz (d₆-DMSO) 7.12 (1H, d), 6.81 (1H, d), 2.29(3H, s).

[0395] b)2-[[(1R)-3-Chloro-1-phenylpropyl]oxy]-5-fluoro-4-methylbenzonitrile

[0396] The subtitle compound was prepared by the method of Example 5(a)using 5-fluoro-2-hydroxy-4-methylbenzonitrile andS-α-(2-chloroethyl)benzenemethanol.

[0397]¹H NMR 300 MHz (CDCl₃) 7.41−7.29 (5H, m), 7.16 (1H, d), 6.63 (1H,d), 5.45 (1H, m), 3.89 (1H, m), 3.63 (1H, m), 2.55 (1H, ), 2.24 (1H, m),2.17 (3H, s).

[0398] c)5-Fluoro-2-[[(1R)-3-iodo-1-phenylpropyl]oxy]-4-methylbenzonitrile

[0399] The subtitle compound was prepared by the method of Example 5(b)using5-fluoro-2-[[(1R)-3-chloro-1-phenylpropyl]oxy]-5-fluoro-4-methylbenzonitrile.

[0400]¹H NMR 300 MHz (CDCl₃) 7.39−7.31 (5H, m), 7.16 (1 H, d), 6.64 (1H,d),5.33 (1H, m), 3.47 (1H, m), 3.28 (1H, m), 2.54 (1H, m), 2.31 (1H, m),2.18 (3H, s).

[0401] d)2-[[(1R)-3-azido-1-phenylpropyl]oxy]-5-fluoro-4-methylbenzonitrile

[0402] The iodo compound 17(c) (504 mg, 1.28 mmol) and sodium azide (124mg, 1.91 mmol) in dimethylsulphoxide (5 ml) and water (2 drops) werestirred for 3 h. The reaction mixture was poured into water, andextracted with ethyl acetate which was then washed with brine and driedover anhydrous magnesium sulphate. The solvent was evaporated to give361 mg (91%) of a pale yellow oil.

[0403]¹H NMR 300 MHz (CDCl₃) 7.39−7.29 (5H, m), 7.16 (1H, d), 6.59 (1H,d), 5.30 (1H, m), 3.67 (1H, m), 3.46 (1H, m), 2.31 (1H, m), 2.17 (3H,t), 2.08 (1H, m).

[0404] e)2-{[(1R)-3-Amino-1-phenylpropyl]oxy}-5-fluoro-4-methylbenzonitrileFumarate

[0405] The azide 17(d) in tetrahydrofuran (15 ml) was treated withtriphenylphosphine (512 mg, 1.95 mmol) followed by water (1.5 ml). Thereaction mixture was heated under reflux with stirring for 2 h,evaporated and the residue eluted down a flash chromatography column,initially using ethyl acetate and then 5% 7M ammonia inmethanol/dichloromethane as eluent to give 186 mg of a viscous oil. Thiswas dissolved in the minimum of ethanol, treated with fumaric acid (75.7mg, 0.652 mmol), warmed to complete solution and treated with etheruntil turbid. After standing for 1 h the crystals were collected byfiltration, washed with a little acetonitrile and dried at 40° C. invacuo to give 159 mg (30%) of the title compound as a colourless solid.

[0406] MS APCI+ve ^(m)/z285 C(M+H)⁺].

[0407]¹H NMR 300 MHz (d₆-DMSO) 7.63 (1H, d), 7.43−7.28 (5H, m), 7.08(1H, d), 6.39 (2H, s), 5.73 (1H, m), 2.87 (2H, t), 2.30−2.03 (2H, m),2.17 (3H, s).

EXAMPLE 18

[0408]4-Chloro-5-fluoro-2-[3-(methylamino)-1-(2-pyrimidinyl)propoxy]benzonitrilehydrochloride

[0409] a) [3-Hydroxy-3-(2-pyrimidinyl)propyl]methylcarbamic acid,1,1-dimethylethyl ester

[0410] To 2-(tributylstannyl)pyrimidine (690 mg, 1.87 mmol) dissolved indry tetrahydrofuran (10 ml) cooled to −78° C. was added 2.4M n-butyllithium in hexanes (0.8 ml, 1.87 mmol) under nitrogen. After stirringfor a further 0.5 h, methyl(3-oxopropyl)carbamic acid, 1,1-dimethylethylester in dry tetrahydrofuran (10 ml) was added rapidly at −78° C. Thereaction mixture was allowed to warm to ambient, treated with aqueoussaturated ammonium chloride solution and extracted with ethyl acetatewhich was washed with brine and dried over anhydrous magnesium sulphate.The solvent was evaporated and the residue eluted down a flashchromatography column using initially 10% ethyl acetate/dichloromethane,then 10% methanol/dichloromethane to give 260 mg (43%) of the subtitlecompound as a viscous yellow oil.

[0411] MS APCI+ve ^(m)/z 268 [(M+H)⁺].

[0412] b)[3-(5-Chloro-2-cyano-4-fluorophenoxy)-3-(2-pyrimidinyl)propyl]methylcarbamicacid, 1,1-dimethylethyl ester

[0413] The alcohol 18(a) (255 mg, 0.955 mmol) in dryN,N-dimethylformamide (15 ml) was treated with sodium hydride (60% inmineral oil, 40 mg, 0.955 mmol) and the reaction mixture stirred undernitrogen until effervescence had ceased.4-Chloro-2,5-difluorobenzonitrile (166 mg, 0.955 mmol) was added and thereaction mixture heated at 40° C. under nitrogen for 1 h. The reactionwas cooled, partitioned between brine and ethyl acetate, the organiclayer separated, washed with water (5x), then brine and dried overanhydrous magnesium sulphate. The solvent was evaporated and the residueeluted down a flash chromatography column using 30% ethylacetate/isohexane as eluent to give 140 mg (35%) of the subtitlecompound as a viscous oil.

[0414]¹H NMR 300 MHz (CDCl₃) 8.76 (2H, d), 7.33 (1H, d), 7.26 (1H, m),6.92 (1H, br m), 5.33 (1H, br m), 3.65 (1H, br m), 3.41 (1H, m), 2.89(3H, s), 2.45−2.30 (2H m), 1.38 (9H, s).

[0415] c)4-Chloro-5-fluoro-2-[3-(methylamino)-1-(2-pyrimidinyl)propoxy]benzonitrilehydrochloride

[0416] The carbamate 18(b) (140 mg, 0.333 mmol) was treated with 4M HClin dioxan (10 ml) and stirred for 1 h. The solid which had precipitatedwas collected by. filtration washed with ether and dried to give 97 mg(80%) of the required product as a colourless solid.

[0417] MS APCI+ve ^(m)/z 321 [(M+H)⁺].

[0418]¹H NMR 300 MHz (d₆-DMSO) 8.98 (2H, br m), 8.88 (2H, d), 8.04 (1H,d), 7.52 (1H, t), 7.41 (1H, d), 5.90 (1H, t), 3.12 (2H, m), 2.58 (2H,t), 2.49 (3H, s).

EXAMPLE 19

[0419]4-Chloro-5-fluoro-2-({(1R)-1-(3-furanyl)-3-[(2-methoxyethyl)amino]propyl}oxy)benzonitrileoxalate

[0420] a) (R)-α-(2-Chloroethyl)-3-furanmethanol

[0421] This was prepared in a two step sequence as for the preparationof Example 74(d) starting from 1-(3-furanyl)-2-propen-1-one, to give acolourless oil.

[0422]¹H NMR 300 MHz (CDCl₃) 7.43−7.41 (2H, m), 6.42 (1H, s), 4.98−4.92(1H, m), 3.79−3.73 (2H, m), 2.30−2.10 (2H, m).

[0423] b) 4-Chloro-5-fluoro-2-({(1R)-1-(3-furanyl)-3-[(2-methoxyethyl)amino]propyl}oxy)benzonitrileoxalate

[0424] (R)-α-(2-Chloroethyl)-3-furanmethanol (100 mg, 0.62 mmol) wasdissolved in tetrahydrofuran (5 ml) at room temperature. To thissolution was added sodium hydride as a 60% suspension in mineral oil (37 mg, 0.93 mmol) and the mixture was stirred for 10 minutes before solid4-chloro-2,5-difluorobenzonitrile (107.6 mg, 0.62 mmol) was added in oneportion. The resultant mixture was stirred for 1 h before water (2 ml)was added and the mixture concentrated in vacuo. The residues werepartitioned between dichloromethane and water. The organics werecollected, dried over magnesium sulphate, filtered and concentrated todryness in vacuo. The resultant residue was dissolved inN,N-dimethylformamide (2 ml) and treated with sodium iodide (93 mg, 0.62mmol), triethylamine (172 μl, 1.24 mmol) and 2-methoxyethanamine (107μl, 1.24 mmol) before being heated to 60° C. for 72 h. After beingallowed to cool the mixture was filtered and purified via reverse phaseHPLC to give the title compound as a free base which was treated with a50% saturated solution of oxalic acid in ether. The resultant whitesolid was collected via filtration to yield the title compound (61 mg,28%).

[0425] MS APCI+ve ^(m)/z 353/355 [(M+H)⁺].

[0426]¹H NMR 300 MHz (d₆-DMSO) 8.02 (1H, d), 7.82 (1H, s), 7.70 (1H, s),7.59 (1H, s), 5.72 (2H, t), 3.57 (2H, m), 3.31 (3H, s), 3.16 (2H, m),3.09−2.98 (2H, b), 2.37 (1H, bm), 2.27 (1H br m).

EXAMPLE 20

[0427]4-Methoxy-2-[[(1R)-3-(methylamino)-1-phenylpropyl]oxy]-benzonitrilehydrochloride

[0428] (a)[(3R)-3-(2-Cyano-5-methoxyphenoxy)-3-phenylpropyl]methylcarbamic acid,1,1-dimethylethyl ester

[0429] To a stirred mixture of 2-cyano-5-methoxyphenol (149 mg, 1.00mmol) and [(3S)-3-hydroxy-3-phenylpropyl]methylcarbamic acid1,1-dimethylethyl ester (265 mg, 1.00 mmol) in tetrahydrofuran (10 ml)under nitrogen was added triphenylphosphine (290 mg, 1.10 mmol) followedby diethyl diazodicarboxylate (1929 mg, 1.10 mmol). The reaction mixturewas stirred at room temperature for 24 h, then evaporated to dryness.The residue was eluted down a flash chromatography column using 30%ethyl acetate/isohexane as eluent to give 275 mg (69%) of the subtitlecompound as an oil.

[0430]¹H NMR 300 MHz (CDCl₃) 7.26-7.45 (6H, m), 6.43 (1H, dd), 6.25 (1H,s), 5.19 (1H, bs), 3.67 (3H, s), 3.50 (2H, bs), 2.87 (3H, s), 2.25 (1H,bs), 2.10 (1H, m), 1.38 (9H, s).

[0431] b)4-Methoxy-2-[[(1R)-3-(methylamino)-1-phenylpropyl]oxy]-benzonitrilefumarate

[0432] [(3R)-3-(2-Cyano-5-methoxyphenoxy)-3-phenylpropyl]methylcarbamicacid, 1,1-dimethylethyl ester (270 mg, 0.682 mmol) was dissolved in 4Mhydrogen chloride in dioxane (8 ml). The resulting solution was stirredat room temperature for 20 h, then diluted with sodium bicarbonatesolution containing ammonia and extracted three times withdichloromethane. The combined organic fractions were washed with brinethen dried over magnesium sulphate. The solvent was evaporated and theresidue dissolved in ethanol.

[0433] To this solution was added fumaric acid in ethanol and thesolvent evaporated. The residue was recrystallised from ethanol/diethylether to give 128 mg (46%) of the title compound as a white solid.

[0434] MS APCI+ve ^(m)/z 297 [(M+H)⁺].

[0435]¹H NMR 300 MHz (d₆-DMSO) 7.62 (1H, d), 7.29-7.44 (5H, m), 6.61(2H, m), 6.44 (2H, s), 5.74 (1H, dd), 3.71 (3H, s), 2.89 (2H, t), 2.50(3H, s), 2.22 (1H, m), 2.11 (1H, m).

EXAMPLE 21

[0436] γ-(2-Bromo-5-fluorophenoxy)-N-methyl-benzenepropanamine fumarate

[0437] Prepared by the method of Example 2(b) using(3-hydroxy-3-phenylpropyl)methylcarbamic acid 1,1-dimethylethyl esterand 2-bromo-5-fluorophenol and converted into the title compound as afumarate salt (white solid) (11.3 mg, 3.2%).

[0438] MS APCI+ve ^(m)/z 338 [(M+H)⁺].

[0439]¹H NMR 300 MHz (d₆-DMSO) 7.61−7.56 (1H, dd), 7.40−7.30 (5H, m),6.90-6.86 (1H, dd), 6.75−6.69 (1H, dt), 6.43 (2H, s), 5.69−5.65 (1H, m),3.35 (3H, s), 2.90−2.845 (2H, t), 2.27−2.06 (2H, m).

EXAMPLE 22

[0440] (R)-γ-(5-Bromo-2-chlorophenoxy)-N-methylbenzenepropanaminefumarate

[0441] [(3S)-3-Hydroxy-3-phenylpropyl]methylcarbamic acid1,1-dimethylethyl ester was reacted with 5-bromo-2-chlorophenol, in asimilar method to that described in Example 2(b) to give the titlecompound as a fumarate salt (white solid) (449 mg, 52%).

[0442]¹H NMR 400 MHz (d₆-DMSO) 7.40−7.36 (5H, m), 7.34−7.29 (1H, m),7.19-7.19 (1H, d). 7.10−7.08 (1H, dd), 6.44 (2H, s), 5.72−5.70 (1H, m),2.90−2.86 (2H, t), 2.52−2.48 (3H, s), 2.29−2.05 (2H, m).

EXAMPLE 23

[0443] (R)-γ-(2-Bromo-5-nitrophenoxy)-N-methylbenzenepropanaminefumarate

[0444] [(3S) -3-Hydroxy-3-phenylpropyl]methylcarbamic acid1,1-dimethylethyl ester was reacted with 2-bromo-5-nitrophenol in asimilar method to that described in Example 2(b) to give the titlecompound as a fumarate salt (yellow solid) (278 mg, 49.8%).

[0445] MS APCI+ve ^(m)/z 365 [(M+H)⁺].

[0446]¹H NMR 300 MHz (d₆-DMSO) 7.91−7.88 (1h, d), 7.72−7.67 (2H, m),7.46−7.28 (5H, m), 6.43 (2H, s), 5.88−5.84 (1H, dd), 2.93−2.89 (2H, t),2.53−2.43 (3H, s), 2.38−2.10 (2H, m).

EXAMPLE 24

[0447]4-Chloro-5-fluoro-2-[[(1R)-3[(2-methoxyethyl)amino]-1-phenylpropyl]oxy]-benzonitrileoxalate

[0448]4-Chloro-5-fluoro-2-[[(1R)-3-iodo-1-phenylpropyl]oxy]-benzonitrile(0.481 mmol, made by method of Example 43(b)) was dissolved in2-methoxyethylamine (2.4 mmol) and the resulting yellow solution stirredat room temperature for 24 h. Excess amine was evaporated and theresidue partitioned between aqueous sodium hydrogen carbonate and ethylacetate. The crude product was extracted into ethyl acetate which wasthen dried over anhydrous sodium sulphate. Filtration followed byevaporation gave an oil which was purified by the use of chromotographyand reverse phase HPLC. The residue was converted into an oxalate saltusing oxalic acid and methanol to give 48 mg (22%) of the titlecompound.

[0449] MS APCI+ve ^(m)/z 363 [(M+H)⁺].

[0450]¹H NMR 400 MHz (d₆-DMSO) 8.03−8.01 (1H, d), 7.45−7.41 (5H, m),7.37−7.32 (1H, m), 5.79−5.76 (1H, m), 3.55−3.52 (2H, t), 3.29 (3H, s),3.11−2.97 (2H, m), 2.52−2.49 (2H, m), 2.34−2.17 (2H, m).

EXAMPLE 25

[0451]4-Chloro-2-{[(1R)-3-(cyclopropylamino)-1-phenylpropyl]oxy}-5-fluorobenzonitrileoxalate

[0452] (R)-α-(2-Chloroethyl)benzenemethanol (341 mg, 2 mmol) wasdissolved in tetrahydrofuran (10 ml) and treated with sodium hydride asa 60% suspension in mineral oil (480 mg, 3 mmol) followed after 10minutes by 4-chloro-2,5-difluorobenzonitrile (347 mg, 2 mmol). Themixture was stirred at room temperature for 18 h before being treatedwith methanol (1 ml) and then water (10 ml). The tetrahydrofuran wasthen removed via heating the vessel to 80° C. and applying a nitrogenstream. Once the tetrahydrofuran was evaporated the residue wasextracted into dichloromethane, dried over magnesium sulphate andconcentrated in vacuo. The resultant material was re-dissolved intodimethylformamide (8 ml) and treated with sodium iodide (305 mg, 2.03mmol), triethylamine (565 μl, 4.06 mmol) and cyclopropylamine (114 mg, 2mmol) before being heated to 60° C. for 5 days. The mixture was filteredand purified via RPHPLC on the crude reaction material. The purifiedcompound was then treated with 50% saturated oxalic acid in ether toproduce 74 mg of a white powder that was collected via filtration.

[0453] MS APCI+ve ^(m)/z 345/347 [(M+H)⁺].

[0454]¹H NMR 400 MHz (d₆-DMSO) 7.97−7.87 (m, 1H), 7.53−7.25 (m, 6H),5.69 (m, 1H), 3.28−3.07 (m, 2H), 2.80−2.68 (m, 1H), 2.45−2.29 (m, 1H),2.29−2.12 (m, 1H), 0.85−0.74 (m, 4H).

EXAMPLE 26

[0455]4-Chloro-2-{[(1R)-3-(cyclopropylamino)-1-(3-furanyl)propyl]oxy}-5-fluorobenzonitrileoxalate

[0456] Prepared by the method of Example 25 using(R)-α-(2-chloroethyl)-3-furanmethanol (321 mg, 2 mmols) and4-chloro-2,5-difluorobenzonitrile (347 mg, 2 mmols) initially beforeconverting into the title compound via in situ conversion to the iodocompound and treatment with cyclopropylamine. The free base was treatedwith a 50% saturated solution of oxalic acid in ether. The resultantwhite solid was collected via filtration to yield the title compound (14mg, 1.6%).

[0457] MS APCI+ve ^(m)/z 335/337 [(M+H)⁺].

[0458]¹H NMR 400 MHz (d₆-DMSO) 8.01 (d, 1H), 7.70 (s, 1H), 7.70 (s, 1H),7.59 (d, 1H), 6.53 (s, 1H), 5.72 (t, 1H), 3.15−2.99 (m, 2H), 2.97−2.87(m, 1H), 2.40−2.26 (m, 1H), 2.24−2.09 (m, 1H), 0.78−0.66 (m, 4H).

EXAMPLE 27

[0459]4-Chloro-2-{[(1R)-3-(cyclopropylamino)-1-(3-thienyl)propyl]oxy}-5-fluorobenzonitrileoxalate

[0460] Prepared by the method of Example 25 using(R)-α-(2-chloroethyl)-3-thiophenemethanol (Example 74(d)) and4-chloro-2,5-difluorobenzonitrile initially before converting into thetitle compound via i7l situ conversion to the iodo compound andtreatment with cyclopropylamine The free base was treated with a 50%saturated solution of oxalic acid in ether. The resultant white solidwas collected via filtration to yield the title compound (24 mg, 3%).

[0461] MS APCI+ve ^(m)/z 351 [(M+H)⁺].

[0462]¹H NMR 400 MHz (d₆-DMSO) 8.02 (d, 1H), 7.60 (s, 2H), 7.50 (d, 1H),7.14 (d, 1H), 5.83 (t, 1H), 3.14−2.99 (m, 2H), 2.76−2.62 (m, 1H),2.42−2.29 (m, 2H), 2.27−2.13 (m,2H), 0.84−0.63 (m, 4H).

EXAMPLE 28

[0463]4-Bromo-2-{[(1R)-3-(cyclopropylamino)-1-(phenyl)propyl]oxy}-5-fluorobenzonitrileoxalate

[0464] Prepared by the method of Example 25 using(R)-α-(2-chloroethyl)benzenemethanol and4-bromo-2,5-difluorobenzonitrile initially before converting into thetitle compound via in situ conversion to the iodo compound and treatmentwith cyclopropylamine. The free base was treated with a 50% saturatedsolution of oxalic acid in ether. The resultant white solid wascollected via filtration to yield the title compound (41 mg, 4.2%).

[0465] MS APCI+ve ^(m)/z 390 [(M+H)⁺].

[0466]¹H NMR 400 MHz (d₆-DMSO) δ7.96 (d, 1H), 7.49 (d, 1H), 7.45−7.39(m, 3H), 7.39−7.31 (m, 2H), 5.82−5.74 (m, 1H), 3.16−3.00 (m, 2H),2.74−2.64 (m, 1H), 2.38−2.25 (m, 1H), 2.24−2.11 (m, 1H), 0.79−0.64 (m,4H).

EXAMPLE 29

[0467]4-Bromo-2-{[(1R)-3-(cyclopropylamino)-1-(3-furanyl)propyloxy}-5-fluorobenzonitrileoxalate

[0468] Prepared by the method of Example 25 using(R)-α-(2-chloroethyl)benzenemethanol and4-bromo-2,5-difluorobenzonitrile initially before converting into thetitle compound via in situ conversion to the iodo compound and treatmentwith cyclopropylamine. The free base was treated with a 50% saturatedsolution of oxalic acid in ether. The resultant white solid wascollected via filtration to yield the title compound (41 mg, 4.2%).

[0469] MS APCI+ve ^(m)/z 380 [(M+H)⁺].

[0470]¹H NMR 400 MHz (d₆-DMSO) 7.95 (d, 1H), 7.81 (s, 1H), 7.71−7.66 (m,2H), 6.53 (s, 1H), 5.77−5.69 (m, 1H), 3.15−2.9 (m, 2H), 2.73−2.65 (m,1H), 2.41−2.29 (m, 1H), 2.25−2.12 (m, 1H), 0.80−0.67 (m, 4H).

EXAMPLE 30

[0471]4-Bromo-2-{[(1R)-3-(cyclopropylamino)-1-(3-thienyl)propyl]oxy}-5-fluorobenzonitrileoxalate

[0472] Prepared by the method of Example 25 using(R)-α-2-chloroethyl)-3-thiphenemethanol and 4-bromo-2,5difluorobenzonitrile initially before converting into the title compoundvia in situ conversion to the iodo compound and treatment withcyclopropylamine. The free base was treated with a 50% saturatedsolution of oxalic acid in ether to yield the title compound (47 mg,4.8%).

[0473] MS APCI+ve ^(m)/z 396 [(M+H)⁺].

[0474]¹H NMR 400 MHz (d₆-DMSO) 7.95 (d, 1H), 7.63−7.57 (m, 3H), 7.14 (d,1H), 5.83 (t, 1H), 3.14−3.00 (m, 2H), 2.73−2.65 (m, 1H), 2.40−2.30 (m,1H), 2.26−2.15 (m, 1H), 0.78−0.67 (m, 4H).

EXAMPLE 31

[0475]4-Chloro-5-fluoro-2-({(1R)-3-[(3-hydroxypropyl)amino]-1-phenylpropyl}oxy)benzonitrileoxalate

[0476] Prepared by the method of Example 25 but treating theintermediate iodo compound with 3-amino-1-propanol (150 mg, 2 mmol) toyield the title compound (67 mg, 7.4%).

[0477] MS APCI+ve ^(m)/z 363/365 [(M+H)⁺].

[0478]¹H NMR 400 MHz (d₆-DMSO) 8.03 (d, 1H), 7.43 (m, 4H), 7.40 (d, 1H),7.35 (m, 1H), 5.81−5.74 (m, 1H), 3.47 (t, 2H), 3.13−3.00 (m, 2H),3.02−2.95 (m, 2H), 2.39−2.27 (m, 1H), 2.23-2.12 (m, 1H), 1.77-1.67 (m,2H).

EXAMPLE 32

[0479]4-Chloro-5-fluoro-2-[[(1R)-1-(3-furanyl)-3-(3-hydroxypropyl)amino]propyl]oxy}benzonitrileoxalate

[0480] Prepared by the method of Example 26 but treating theintermediate iodo compound with 3-amino-1-propanol (150 m, 2mmol) toyield the title compound (49 mg, 5.5%).

[0481] MS APCI+ve ^(m)/z 353/355 [(M+H)⁺].

[0482] 1H NMR 400 MHz (d₆-DMSO) 8.01 (d, 1H), 7.81 (s, 1H), 7.70−7.69(m, 1H), 7.59 (d, 1H), 6.54−6.53 (m, 1H), 5.76−5.71 (m, 1H), 3.48 (t,2H), 3.07−3.01 (m, 2H), 3.02−2.97 (m, 2H), 2.41−2.31 (m, 1H), 2.26−2.15(m, 1H), 1.78−1.69 (m, 2H).

EXAMPLE 33

[0483]4-Chloro-5-fluoro-2-{[(1R)-3-[(3-hydroxypropyl)amino]-1-(3-thienyl)propyl]oxy}benzonitrileoxalate

[0484] Prepared by the method of Example 27 but treating theintermediate iodo compound with 3-amino-1-propanol (150 mg, 2 mmol) toyield the title compound (74 mg, 8%).

[0485] MS APCI+ve ^(m)/z 369 [(M+H)⁺].

[0486]¹H NMR 400 MHz (d₆-DMSO) 8.02 (d, 1H), 7.62−7.60 (m, 2H), 7.50 (d,1H), 7.16−7.13 (m, 1H), 5.87−5.82 (m, 1H), 3.47 (t, 2H), 3.09−3.02 (M,2h), 3.02−2.96 (m, 2H), 2.42−2.32 (m, 1H), 2.27−2.16 (m, 1H), 1.77−1.68(m, 2H).

EXAMPLE 34

[0487]4-Bromo-5-fluoro-2-({(1R)-3-[(3-hydroxypropyl)amino]-1-phenylpropyl}oxy)benzonitrileoxalate

[0488] Prepared by the method of Example 28 but treating theintermediate iodo compound with 3-amino-1-propanol (150 mg, 2 mmol) toyield the title compound (25 mg, 2.5%).

[0489] MS APCI+ve ^(m)/z 407/409 [(M+H)⁺].

[0490]¹H NMR 400 MHz (d₆-DMSO) 7.97 (d, 1H), 7.49 (d, 1H), 7.45−7.40 (m,4H), 7.39−7.32 (m, 2H), 5.80−5.74 (m, 1H), 3.47 (t, 2H), 3.13−3.03 (m,2H), 3.02−2.96 (m, 2H), 2.38−2.28 (m, 1H), 2.23−2.14 (m, 1H), 1.77−1.68(m, 2H).

EXAMPLE 35

[0491]4-Bromo-5-fluoro-2-({(1R)-1-(3-furanyl)-3-[(3-hydroxypropyl)amino]propyl}oxy)benzonitrileoxalate

[0492] Prepared by the method of Example 29 but treating theintermediate iodo compound with 3-amino-1-propanol (150 mg, 2 mmol) toyield the title compound (42 mg, 4.3%).

[0493] MS APCI+ve ^(m)/z 399/401 [(M+H)⁺].

[0494]¹H NMR 400 MHz (d₆-DMSO) 7.94 (d, 1H), 7.81−7.80 (m, 1H),7.71−7.67 (m, 2H), 6.54−6.52 (m, 1H), 5.74 (t, 1H), 3.48 (t, 2H),3.10−3.01 (m, 2H), 3.02−2.97 (m, 2H), 2.42−2.31 (m, 1H), 2.26−2.16 (m,1H), 1.78−1.70 (m, 2H).

EXAMPLE 36

[0495]4-Bromo-5-fluoro-2-{[(1R)-3-[(3-hydroxypropyl)amino]-1-(3-thienyl)propyl]oxy}benzonitrileoxalate

[0496] Prepared by the method of Example 30 but treating theintermediate iodo compound with 3-amino-1-propanol (150 mg, 2 mmol) toyield the title compound (42 mg, 4.3%).

[0497] MS APCI+ve ^(m)/z 414/416 [(M+H)⁺].

[0498]¹H NMR 400 MHz (d₆-DMSO) 7.95 (d, 1H), 7.64−7.57 (m, 3H),7.16−7.12 (m, 1H), 5.88−5.81 (m, 1H), 3.47 (t, 2H), 3.10−3.01 (m, 2H),3.02−2.97 (m, 2H), 2.42−2.30 (m, 1H), 2.28−2.16 (m, 1H), 1.78−1.68 (m,2H).

EXAMPLE 37

[0499]2-[[(1R)-3-Amino-1-phenylpropyl]oxy]-4-(trifluoromethyl)benzonitrileoxalate

[0500] a) (R)-α-(2-Azidoethyl)benzenemethanol

[0501] (R)-α-(2-Chloroethyl)benzenemethanol (0.73 g, 4.3 mmol) andsodium azide (417 mg, 1.5 eq.) in DMSO (3 ml) was stirred and heated at40° C. for 1.5 h. The reaction mixture was diluted with water (50 ml)and the products extracted into ethyl acetate(2×75 ml). The combinedextracts were dried (magnesium sulphate) and concentrated to an oil.Purification was achieved on silica gel eluting with 50% diethylether/isohexane to afford the azide as a colourless oil (0.6 g, 79%).

[0502]¹H NMR 300 MHz (CDCl₃) 7.61−7.27 (5H, m), 4.88−4.82 (1H, m),3.55−3.35 (2H, m), 2.11−1.89 (2H, m).

[0503] b)2-[[(1R)-3-Azido-1-phenylpropyl]oxy]-4-(trifluoromethyl)benzonitrile

[0504] A mixture of the azido alcohol 37(a) (0.49 g, 2.77 mmol) and2-fluoro-4-(trifluoromethyl)benzonitrile (0.523 g, 2.77 mmol) in drytetrahydrofuran (30 ml) under a nitrogen atmosphere was treated withsodium hydride (60% dispersion, 111 mg, 2.77 mmol). The mixture wasstirred and heated 60° C. for 1.5 h, then quenched with water (150 ml).The products were extracted into diethyl ether (2×100 ml). The combinedextracts were dried over magnesium sulphate, filtered and concentratedto. an oil. The crude material was purified on silica gel using 10%ether/isohexane to afford the title compound as a colourless oil (770mg, 80%).

[0505] MS APCI+ve ^(m)/z 319 [(M+H−28)].

[0506] c)2-[[(1R)-3-Amino-1-phenylpropyl]oxy]-4-(trifluoromethyl)benzonitrileoxalate

[0507] A solution of2-[[(1R)-3-azido-1-phenylpropyl]oxy]-4-(trifluoromethyl)benzonitrile(7.70 mg, 2.2 mmol) in tetrahydrofuran (50 ml) was treated withtriphenylphosphine (1.5 eq.) and water (0.5 ml). The mixture was stirredat ambient temperature for 24 h then concentrated to an oil. The crudeamine was purified on silica gel eluting with ethyl acetate, then 10% 7Nammonia in methanol/dichloromethane. The oil obtained was converted intoan oxalate salt using 1 equivalent of oxalic acid in ethanol to affordthe title compound as a colourless solid (510 mg, 56%).

[0508] MS APCI+ve ^(m)/z 321 [(M+H)⁺].

[0509]¹H NMR 300 MHz (d₆-DMSO) 8.0 (1H, d), 7.44−7.31 (7H, m), 5.93 (1H,dd), 3.04−2.9 (2H, m), 2.4−2.1 (2H, m).

EXAMPLE 38

[0510] 2-[[(1R)-3-Amino-1-phenylpropyl]oxy]-4-chlorobenzonitrile

[0511] a) 2-[[(1R)-3-Azido-1-phenylpropyl]oxy]-4-chlorobenzonitrile

[0512] The sub title compound was prepared by the method of Example37(b) but using 4-chloro-2-fluorobenzonitrile.

[0513]¹H NMR 400 MHz (CDCl₃) 7.48−7.32 (6H, m), 6.95 (1H, dd), 6.79 (1H,d), 5.34 (1H, dd), 3.69−3.63 (1H, m), 3.5−3.44 (1H, m), 2.39−2.32 (1H,m), 2.14−2.05 (1H, m).

[0514] b) 2-[[(1R)-3-Amino-1-phenylpropyl]oxy]-4-chlorobenzonitrileoxalate

[0515] The sub title compound was prepared by the method of Example37(c) but using2-[[(1R)-3-azido-1-phenylpropyl]oxy]-4-chlorobenzonitrile.

[0516] MS APCI+ve ^(m)/z 287/9 [(M+H)⁺].

[0517]¹H NMR 400 MHz (d₆-DMSO) 7.79 (1H, d), 7.46−731 (5H, m), 7.19−7.14(2H, m), 5.81 (1H, dd), 3.01−2.74 (2H, m), 2.35−2.08 (2H, m).

EXAMPLE 39

[0518]4-Chloro-5-fluoro-2-[[(1R)-3-(methylamino)-1-phenylpropyl]oxy]benzonitrile

[0519] a)[(3R)-3-(5-Chloro-2-cyano-4-fluorophenoxy)-3-phenylpropyl]methylcarbamic acid 1,1-dimethylethyl ester

[0520] The sub title compound was prepared by the method of Example 3(b)using 4-chloro-2,5-difluorobenzonitrile and dimethylformamide assolvent.

[0521] MS APCI+ve ^(m)/z 319/21 [(M−(C₄H₉)+H)⁺].

[0522] b)4-Chloro-5-fluoro-2-[[(1R)-3-(methylamino)-1-phenylpropyl]oxy]benzonitrileoxalate

[0523] [(3R)-3-(5-Chloro-2-cyano-4-fluorophenoxy)-3-phenylpropyl]methylcarbamic acid 1,1-dimethylethyl ester (220 mg, 0.525 mmol) was stirredin a 4N solution of hydrogen chloride in dioxan (20 ml) for 20 minutes.The hydrochloride salt was,applied to a silica gel column and elutedwith 10% 7N anmmonia in methanol/dichloromethane. The free base was thenconverted into an oxalate salt with 1 equivalent of oxalic acid inethanol. The title compound was obtained as a colourless solid (175 mg,82%).

[0524] MS APCI+ve ^(m)/z 319/321[(M+H)⁺].

[0525]¹H NMR 300 MHz (d₆-DMSO) 8.02 (1H, d), 7.43−7.31 (6H, m), 5.79(1H, dd), 3.09−2.93 (2H, m), 2.53 (3H, s), 2.4−2.1 (2H, m).

EXAMPLE 40

[0526]2-[[(1R)-3-Amino-1-phenylpropyl]oxy]-4-chloro-5-fluorobenzonitrileoxalate

[0527] a)2-[[(1R)-3-Azido-1-phenylpropyl]oxy]-4-chloro-5-fluorobenzonitrile

[0528] A mixture of the azido alcohol 37(a) (8 g, 0.045 mol) and4-chloro-2,5-difluorobenzonitrile (7.83 g, 0.045 mol) in drydimethylformamide (70 ml) under nitrogen atmosphere was treated withsodium hydride (60% dispersion, 1.81 g, 0.045 mol). The mixture wasstirred and heated to 60° C. for 2 h, then quenched with water (500 ml).The products were extracted into diethyl ether (2×300 ml). The combinedextracts were dried over magnesium sulphate, filtered and concentratedto an oil. The crude material was purified on silica gel using 20%ether/isohexane to afford the title compound as a colourless oil (9.4 g,80%).

[0529]¹H NMR 300 MHz (CDCl₃) 7.43−7.3 (6H, m), 6.84 (1H, dd), 5.29 (1H,dd), 3.7−3.42 (2H, M), 2.4−2.04 (2H, m).

[0530] b) 2-[[(1R)-3-Amino-1-phenylpropyl]oxy]-4-chloro-5-fluorobenzonitrile oxalate

[0531]2-[[(1R)-3-Azido-1-phenylpropyl]oxy]-4-chloro-5-fluorobenzonitrile(Example 40(a)) was reduced in an analogous procedure to that describedfor Example 37(c).

[0532] MS APCI+ve ^(m)/z 305/7 [(M+H)⁺].

[0533]¹H NMR 400 MHz (d₆-DMSO) 8.01 (1H, d), 7.44−7.31 (6H, m), 5.78(1H, dd), 2.91−2.81 (2H, m), 2.28−2.05 (2H, m).

EXAMPLE 41

[0534]γ-[5-Chloro-2-(trifluoromethyl)phenoxy]-N-methylbenzenepropanaminehydrochloride

[0535] The title compound was prepared by the method of Example 3(b)using racemic (3-hydroxy-3-phenylpropyl)carbamic acid 1,1-dimethylethylester and 2,4-dichloro-1-(trifluoromethyl)benzene to give 70 mg of theproduct as a colourless solid.

[0536] MS APCI+ve ^(m)/z 344/6 [(M+H)⁺].

[0537]¹H NMR 300 MHz (d₆-DMSO) 8.93−8.79 (m, 2H), 7.65 (d, 1H),7.45−7.39 (m, 4H), 7.38−7.30 (m, 1H), 7.15 (s, 1H), 7.13 (d, 1H), 5.88(dd, 1H), 3.01−2.90 (m, 2H), 2.55 (s, 3H), 2.37−2.12 (m, 2H).

EXAMPLE 42

[0538]2-[[(1R)-3-(Methylamino)-1-phenylpropyl]oxy]-4-(trifluoromethyl)benzonitrilehydrochloride

[0539] The title compound was prepared by the method of Example 3(b)using 2-fluoro-4-(trifluoromethyl)benzonitrile to give 290 mg of theproduct as a white solid.

[0540] MS APCI+ve ^(m)/z 335 [(M+H)⁺].

[0541]¹H NMR 400 MHz (d₆-DMSO) 9.12−8.99 (m, 2H), 8.00 (d, 1H),7.50−7.30 (m, 7H), 6.06 (dd, 1H), 3.10−2.96 (m, 2H), 2.57 (s, 3H),2.46−2.20 (m, 2H).

EXAMPLE 43

[0542]4-Chloro-5-fluoro-2-[[(1R)-3-[[(5-methylpyrazinyl)methyl]amino]-1-phenylpropyl]oxy]benzonitriledihydrochloride

[0543] a)4-Chloro-2-[[(1R)-3-chloro-1-phenylpropyl]oxy]-5-fluorobenzonitrile

[0544] 4-Chloro-2,5-difluorobenzonitrile (1.0 g, 5.8 mmol) andS-α-(2-chloroethyl)benzene methanol (1.0 g, 5.86 mmol) were dissolved indimethylformamide (10 ml) and 60% NaH (350 mg, 8.7 mmol) addedportionwise over 5 minutes. The mixture was stirred for 2 h, quenchedwith water and extracted with ethyl acetate. The extracts were washedwith water (×3), dried over magnesium sulphate, filtered and evaporated.Purification by flash chromatography (5% ethyl acetate/hexane) gave 1.8g (96%) of the product as a colourless oil.

[0545]¹H NMR 300 MHz (CDCl₃) 7.44−7.32 (m, 5H), 7.31 (d, 1H), 6.87 (d,1H), 5.44 (dd, 1H), 3.93−3.82 (m, 1H), 3.67−3.57 (m, 1H), 2.64−2.51 (m,1H), 2.31−2.18 )m, 1H).

[0546] b)4-Chloro-5-fluoro-2-{[(1R)-3-iodo-1-phenylpropyl]oxy}benzonitrile

[0547]4-Chloro-2-{[(1R)-3-chloro-1-phenylpropyl]oxy}-5-fluorobenzonitrile (1.8, 5.6 mmol) and sodium iodide (12.8 g, 100 mmol) were dissolved inacetone (50 ml) and heated under reflux for 24 h. The reaction mixturewas cooled, filtered and evaporated. The semi-solid residue wasdissolved in toluene, filtered and evaporated again to give 2.3 g of thecrude product as a yellow oil. This was used without purification forthe next step.

[0548] c)4-Chloro-5-fluoro-2-[[(1R)-3-[[(5-methylpyrazinyl)methyl]amino]-1-phenylpropyl]oxy]benzonitriledihydrochloride

[0549] 4-Chloro-5-fluoro-2-{[(1R)-3-iodo-1-phenylpropyl]oxy}benzonitrile(200 mg, 0.48 mmol), 5-methyl-2-pyrazinemethanamine (120 mg, 0.96 mmol)and triethylamine (335 μl, 2.4 mmol) were stirred in DMSO (5 ml) for 48h. The mixture was washed with water and purified by chromatography (5%1M ammonia-methanol/dichloromethane). The eluent was evaporated and theresidue treated with 4M hydrogen chloride in dioxan (5 ml). The solventwas evaporated, azeotroped twice with toluene and triturated with etherto give the required product as a white solid.

[0550] MS APCI+ve ^(m)/z 411 [(M+H)⁺].

[0551]¹H NMR 400 MHz (d₆-DMSO) 8.71 (s, 1H), 8.58 (s, 1H), 8.01 (d, 1H),7.49 (d, 1H), 7.46−7.30 (m, 5H), 5.96 (dd, 1H), 4.36 (t, 2H), 3.20−3.02(m, 2H), 2.53 (s, 3H), 2.52−2.28 (m, 2H).

EXAMPLE 44

[0552]4-Chloro-5-fluoro-2-[[(1R)-3-[(1H-imidazol-2-ylmethyl)amino]-1-phenylpropyl]oxy]benzonitriledihydrochloride

[0553] The title compound was prepared by the method of Example 43(c)using 1H-imidazole-2-methanamine to give the title product as a whitesolid.

[0554] MS APCI+ve ^(m)/z 385 [(M+H)⁺].

[0555]¹H NMR 400 MHz (d₆-DMSO) 8.01 (d, 1H), 7.72 (s, 2H), 7.51 (d, 2H),7.49−7.32 (m, 5H), 6.00 (dd, 1H), 4.54 (s, 2H), 3.26−3.12 (m, 2H),2.50−2.25 (m, 2H).

EXAMPLE 45

[0556]2-[[(1R)-3-Amino-1-(3-isoxazolyl)propyl]oxy]-4-(trifluoromethyl)-benzonitrilefumarate

[0557] a)2-[[(1R)-3-Azido-1-(3-isoxazolyl)propyl]oxy]-4-(trifluoromethyl)benzonitrile

[0558] The product from Example 93(a) (0.17 g) was reacted with4-(trifluoromethyl)-2-fluoro-benzonitrile (0.3 g) using the proceduredescribed in Example 93(b) to afford the product as a gum which wascarried on directly to the next step.

[0559] b)2-[[(1R)-3-Amino-1-(3-isoxazolyl)propyl]oxy]-4-(trifluoromethyl)benzonitrilefumarate

[0560] The product from step (a) was subjected to the proceduredescribed in Example 90(b) to afford the product as a solid (0.1 g).

[0561] MS APCI+ve ^(m)/z 312 [(M+H)⁺].

[0562]¹H NMR 300 MHz (d₆-DMSO) 8.99 (1H, d), 8.03 (1H, d), 7.60 (1H, s),7.50 (1H, d), 6.74 (1H, d), 6.43 (2H, s), 6.24−6.15 (1H, m), 2.98 (2H,dd), 2.48−2.35 (1H, m), 2.34−2.21 (1H, m).

EXAMPLE 46

[0563]4-Chloro-2-[[(1R)-3-[[2-(dimethylamino)ethyl]amino]-1-phenylpropyl]oxy]-5-fluorobenzonitrile dihydrochloride

[0564] The title compound was prepared by the method of Example 43(c)using N¹,N¹-dimethyl-1,2-ethanediamine to give the product as a whitesolid.

[0565] MS APCI+ve ^(m)/z 376 [(M+H)⁺].

[0566]¹H NMR 400 MHz (d₆-DMSO) 8.02 (d, 1H), 7.52 (d, 1H), 7.48−7.32 (m,5H), 5.95 (dd, 3H), 3.47−3.39 (m, 2H), 3.39−3.30 (m, 2H), 3.19−3.03 (m,2H), 2.83 (s, 6H), 2.47−2.22 (m, 2H).

EXAMPLE 47

[0567]4-Chloro-5-fluoro-2-[[(1R)-3-[[2-(4-morpholinyl)ethyl]amino]-1-phenylpropyl]oxy]benzonitriledihydrochloride

[0568] The title compound was prepared by the method of Example 43(c)using 4-morpholineethanamine to give the product as a white solid.

[0569] MS APCI+ve ^(m)/z 418 ([M+H]⁺].

[0570]¹H NMR 400 MHz (d₆-DMSO) 9.75−9.50 (m, 2H), 8.02 (d, 1H), 7.51 (d,1H), 7.48−7.32 (m, 5H), 5.95 (dd, 1H), 4.07−3.91 (m, 2H), 3.86−3.70 (m,2H), 3,61−3.34 (m, 6H), 3.22−3.01 (m, 4H), 2.50−2.20 (m, 2H).

EXAMPLE 48

[0571]4-Chloro-5-fluoro-2-[[(1R)-3-[[2-(1H-imidazol-1-yl)ethyl]amino]-1-phenylpropyl]oxy]benzonitriledihydrochloride

[0572] The title compound was prepared by the method of Example 43(c)using 1H-imidazole-1-ethanamine to give the product as a white solid.

[0573] MS APCI+ve ^(m)/z 399 [(M+H)⁻].

[0574]¹H NMR 300 MHz (d₆-DMSO) 9.17−9.12 (m, 1H), 8.01 (d, 1H),7.82−7.78 (m, 1H), 7.69−7.65 (m, 1H), 7.53 (d, 1H), 7.49−7.30 (m, 5H),5.98 (dd, 1H), 4.61 (t, 2H), 3.50 (t, 2H), 3.13−2.99 (m, 2H), 2.45−2.22(m, 2H).

EXAMPLE 49

[0575] 4-Chloro-5-fluoro-2-[[(1R)-3-[[2-(1H-imidazol-4-yl)ethyl]amino]-1-phenylpropyl]oxy]benzonitriledihydrochloride

[0576] The title compound was prepared by the method of Example 43(c)using 1H-imidazole-4-ethanamine to give the product as a white solid.

[0577] MS APCI+ve ^(m)/z 399 [(M+H)⁻].

EXAMPLE 50

[0578]4-Chloro-5-fluoro-2-[[(1R)-3-[(2-hydroxyethyl)amino]-1-phenylpropyl]oxy]benzonitrilehydrochloride

[0579] The title compound was prepared by the method of Example 43(c)using 2-aminoethanol to give the product as a white solid.

[0580] MS APCI+ve ^(m)/z 349 [(M+H)⁻].

[0581]¹H NMR 400 MHz (d₆-DMSO) 9.10−8.90 (m, 2H), 8.02 (d, 1H), 7.49 (d,1H), 7.47−7.39 (m, 4H), 7.38−7.32 (m, 1H), 5.91 (dd, 1H), 5.26 (t, 2H),3.67 (q, 2H), 3.13−2.96 (m, 2H), 2.46−2.21 (m, 2H).

EXAMPLE 51

[0582]2-[[(1R)-3-[(2-Aminoethyl)amino]-1-phenylpropyl]oxy]-4-chloro-5-fluorobenzonitriledihydrochloride

[0583] The title compound was prepared by the method of Example 43(c)using 1,2-ethanediamine to give the product as a white solid.

[0584] MS APCI+ve /z 348 [(M+H)⁺].

[0585]¹H NMR 400 MHz (d₆-DMSO) 8.01 (d, 1H), 7.51 (d, 1H), 7.48−7.32 (m,5H), 5.98 (dd 1H), 3.37−3.30 (m, 2H), 3.26−3.16 (m, 2H), 3.13−3.04 (m,2H), 2.48−2.20 (m, 2).

EXAMPLE 52

[0586] 4-Chloro-5-fluoro-2-[[(1R)-1-phenyl-3-[(33.3-trifluoropropyl)amino]propyl]oxy]benzonitrile trifluoroacetate

[0587]2-[[(1R)-3-Amino-1-phenylpropyl]oxy]-4-chloro-5-fluorobenzonitrile (300mg, 0.99 mmol) and 3,3,3-trifluoropropanal (123 mg, 1.2 mmol) weredissolved in dichloromethane (10 ml), 4A sieves added, followed bysodium triacetoxyborohydride (320 mg, 1.5 mmol) and stirred for 20 h.The reaction mixture was washed with saturated aqueous sodium hydrogencarbonate, dried over magnesium sulphate, filtered and evaporated. Theresidue was purified by reverse phase chromatography (0.1% aqueoustrifluoroacetic acid/methanol) to give 280 mg of the product as a whitesolid.

[0588] MS APCI+ve ^(m)/z 401 [(M+H)⁺].

[0589]¹H NMR 300 MHz (d₆-DMSO) 8.99−8.82 (m, 2H), 8.04 (d, 5H),7.48−7.30 (m, 2H), 5.78 (dd, 1H), 3.26 (t, 2H), 3.21−3.03 (m, 2H),2.79−2.61 (m, 2H), 2.43−2.13 (m, 2H).

EXAMPLE 53

[0590] 2-{[(1R)-3-amino-1-(2-thiazolyl)propyl]oxy}-4-chlorobenzonitrilehydrochloride.

[0591] a) [3-Oxo-3-(2-thiazolyl)propyl]carbamic acid 1,1-dimethylethylester

[0592] To a solution of 2-bromothiazole (5.035 g, 30.7 mmol) in drytetrahydrofuran (125 ml) at −78° C. under nitrogen was added a solutionof n-butyllithium in hexanes (1.6 M, 17.6 ml, 28.2 mmol) over a periodof 30 minutes, followed by a solution of[3-(methoxymethylamino)-3-oxopropyl]carbamic acid 1,1-dimethylethylester (2.976 g, 12.8 mmol) in dry tetrahydrofuran (30 ml) added over 30minutes. The reaction mixture was allowed to warm up to 0° C., quenchedwith saturated ammonium chloride and extracted with ethyl acetate (3×100ml). The combined extracts were washed with water (3×50 ml) andsaturated brine solution (1×100 ml), dried (magnesium sulphate) andconcentrated in vacuo to leave a crude orange oil. Flash chromatography(silica, 25% ethyl acetate in isohexane) gave 2.2 g of a pale yellow oil(67%).

[0593] MS APCI+ve ^(m)/z 201 ([(M(—C₄H₉)+H)⁺].

[0594]¹H NMR 300 MHz (CDCl₃) 8.01 (1H, m), 7.69 (1H, m), 5.05 (1H, brs), 3.57 (2H, q), 3.39 (2H, t), 1.46 (9H, s).

[0595] b) [(3R)-3-Hydroxy-3-(2-thiazolyl)propyl]carbamic acid1,1-dimethylethyl ester

[0596] To a solution of (S)-3-methyl-CBS-oxazaborolidine (1M solution intoluene, 0.43 ml) in dry tetrahydrofuran (30 ml) at −10° C. undernitrogen, was added borane-tetrahydrofuran complex (1M intetrahydrofuran, 2.58 ml) and stirred at −10° C. for 15 minutes. Asolution of [3-oxo-3-(2-thiazolyl)propyl]carbamic acid 1,1-dimethylethylester (1.1 g, 4.3 mmol) in dry tetrahydrofuran (20 ml) was addeddropwise over 45 minutes and the resulting mixture was allowed to warmup to room temperature over 16 h. Methanol (10 ml) was added and themixture was stirred at room temperature for 15 minutes before thesolvent was removed at reduced pressure. Methanol (10 ml) was againadded and removed at reduced pressure to leave a crude yellow oil. Flashchromatography (silica, 25 to 100% ethyl acetate in isohexane) gave 0.75g of a clear gum (67%).

[0597] MS APCI+ve ^(m)/z 259 [(M+H)⁺].

[0598]¹H NMR 300 MHz (CDCl₃) 7.72 (1H, d), 7.29 (1H, d), 5.06−5.02 (1H,m), 4.92 (1H, br s), 4.71 (1H, s), 3.70−3.58 (1H, m), 3.25−3.16 (1H, m),2.24 (1H, m), 1.93−1.87 (1H, m), 1.44 (9H, s).

[0599] c)[(3R)-3-(5-Chloro-2-cyanophenoxy)-3-(2-thiazolyl)propyl]carbamic acid1,1-dimethylethyl ester.

[0600] To a solution of 4-chloro-2-fluorobenzonitrile (156 mg, 1 mmol)and [(3R)-3-hydroxy-3-(2-thiazolyl)propyl]carbamic acid1,1-dimethylethyl ester (258 mg, 1 mmol) in dry dimethylformamide (3ml), was added sodium hydride (60% dispersion in oil, 40 mg, 1 mmol) andthe mixture was stirred at room temperature for 16 h. The reaction wasquenched with methanol and partitioned between ethyl acetate and water.The combined extracts were washed with water (3×25 ml) and saturatedbrine solution, dried (magnesium sulphate) and concentrated in vacuo toleave a crude yellow gum. Flash chromatography (silica, 15% ethylacetate in isohexane) gave 345 mg of a white solid (86%).

[0601] MS APCI+ve ^(m)/z 394/396 [(M+H)⁺].

[0602]¹H NMR 300 MHz (CDCl₃) 7.79 (1H, d), 7.49 (1H, d), 7.38 (1H, d),7.06 (1H, d), 7.02 (1H, dd), 5.72 (1H, dd), 4.80 (1H, bd s), 3.56−3.20(2H, m), 2.50−2.20 (2H, m), 1.44 (9H, s).

[0603] d)2-{[(1R)-3-Amino-1-(2-thiazolyl)propyl]oxy}-4-chlorobenzonitrilehydrochloride

[0604] To a solution of[(3R)-3-(5-chloro-2-cyanophenoxy)-3-(2-thiazolyl)propyl]-carbamic acid1,1-dimethylethyl ester (140 mg, 0.36 mmol) in dry dioxan (3 ml) wasadded 4M HCl in dioxan (1 ml) and the mixture was stirred at roomtemperature for 16 h. The precipitate was collected, washed with ethylacetate and vacuum dried to leave 106 mg of a white solid (90%).

[0605] MS APCI+ve ^(m)/z 294/296 [(M+H)⁺].

[0606]¹H NMR 300 MHz (d₆-DMSO) δppm: 8.16 (3H, br s), 7.90−7.83 (3H, m),7.52 (1H, d), 7.26 (1H, dd), 6.31 (1H, dd), 3.10−2.96 (2H, m), 2.48−2.38(2H, m).

EXAMPLE 54

[0607]4-Chloro-2-{[(1R)-3-(methylamino)-1-(2-thiazolyl)propyl]oxy}benzonitrilehydrochloride

[0608] a)[(3R)-3-(5-Chloro-2-cyanophenoxy)-3-(2-thiazolyl)propyl]methylcarbamicacid 1,1-dimethylethyl ester

[0609] To a solution of[(3R)-3-(5-chloro-2-cyanophenoxy)-3-(2-thiazolyl)propyl]-carbamic acid1,1-dimethylethyl ester (200 mg, 0.51 mmol) in dry tetrahydrofuran (10ml), was added sodium hydride (56 mg, 60% dispersion in oil, 1.41 mmol)and stirred at room temperature for 15 minutes. Iodomethane (1.325 g,0.58 ml, 4.7 mmol) was added. The reaction was stirred at roomtemperature for 18 h, quenched with saturated ammonium chloride solutionand partitioned between ethyl acetate and water. The combined extractswere washed with water (3×25 ml) and saturated brine solution, dried(magnesium sulphate) and concentrated in vacuo to leave a crude yellowgum. Flash chromatography (silica, 25% ethyl acetate in isohexane)afforded 175 mg of an opaque oil (98%).

[0610] MS APCI+ve ^(m)/z 408/410 [(M+H)⁺].

[0611]¹H NMR 300 MHz (CDCl₃) 7.79 (1H, d), 7.49 (1H, d), 7.37 (1H, d),7.07 (1H, s), 7.01 (1H, d), 5.68−5.63 (1H, m), 3.70−3.56 (1H, m),3.43−3.33 (1H, m), 2.88 (3H, s), 2.45−2.28 (2H, m), 1.44 (9H, s).

[0612] b)4-Chloro-2-{[(1R)-3-(methylamino)-1-(2-thiazolyl)propyl]oxy}benzonitrilehydrochloride

[0613] The title compound was made using the same method as in Example53(d) to give 175 mg of a white solid (99%).

[0614] MS APCI+ve ^(m)/z 308/310 [(M+H)⁺].

[0615]¹H NMR 300 MHz (d₆-DMSO) 7.90−7.83 (3H, m), 7.56−7.51 (1H, m),7.27 (1H, d), 6.35−6.25 (1H, m), 3.29 (3H, s), 3.09 (2H, t), 2.60−2.54(2H, m).

EXAMPLE 55

[0616] (R)-γ-(2.5-Dichlorophenoxy)-2-thiazolepropanamine hydrochloride

[0617] a) [(3S-3-Hydroxy-3-(2-thiazolyl)propyl]carbamic acid1,1-dimethylethyl ester

[0618] To a solution of (R)-3-methyl-CBS-oxazaborolidine (1M solution intoluene, 0.43 ml) in dry tetrahydrofuran (30 ml) at −10° C. undernitrogen was added borane-tetrahydrofuran complex (1M intetrahydrofuran, 2.58 ml) and stirred at −10° C. for 15 minutes. Asolution of [3-oxo-3-(2-thiazolyl)propyl]carbamic acid 1,1-dimethylethylester (1.1 g, 4.3 mmol) in dry tetrahydrofuran (20 ml) was addeddropwise over 45 minutes and the resulting mixture was allowed to warmup to room temperature over 16 h. Methanol (10 ml) was added and themixture was stirred at room temperature for 15 minutes before thesolvent was removed at reduced pressure. Methanol (10 ml) was againadded and removed at reduced pressure to leave a crude yellow oil. Flashchromatography (silica, 25 to 100% ethyl acetate in isohexane) afforded0.74 g (67%) of a clear gum.

[0619] MS APCI+ve ^(m)/z 259 [(M+H)⁺].

[0620]¹H NMR 300 MHz (CDCl₃) 7.72 (1H, d), 7.29 (1H, d), 5.06−5.02 (1H,m), 4.95 (1H, bd s), 4.75 (1H, s), 3.70−3.58 (1H, m), 3.25−3.16 (1H, m),2.24−2.16 (1H, m), 1.93−1.87 (1H, m), 1.44 (9H, s).

[0621] b) [(3R)-3-(2,5-Dichlorophenoxy)-3-(2-thiazolyl)propyl]carbamicacid 1,1-dimethylethyl ester.

[0622] To a solution of 2,5-dichlorophenol (163 mg, 1 mmol)[(3S)-3-hydroxy-3-(2-thiazolyl)propyl]carbamic acid 1,1-dimethylethylester (258 mg, 1 mmol) and triphenylphosphine (315 mg, 1.2 mmol) in drytetrahydrofuran (30 ml) at 0° C. under nitrogen, was added diisopropylazodicarboxylate (243 mg, 0.24 ml, 1.2 mmol) dropwise over 5 minutes.The mixture was stirred at room temperature for 16 h before the reactionwas concentrated in vacuo to leave a crude yellow gum. Flashchromatography (silica, 15% ethyl acetate in isohexane) afforded 245 mgof a clear oil (63%).

[0623] MS APCI+ve ^(m)/z 403/405/407 [(M+H)⁺].

[0624]¹H NMR 300 MHz (CDCl₃) 7.79 (1H, d), 7.35 (1H, d), 7.29 (1H, d),6.93 (1H, d), 6.90 (1H, dd), 5.66 (1H, dd), 5.03 (1H, bd s), 3.50−3.20(2H, m), 2.45−2.25 (2H, m), 1.43 (9H, s).

[0625] c) (R)-γ-(2,5-Dichlorophenoxy)-2-thiazolepropanaminehydrochloride

[0626] The title compound was made using the method of Example 53(d) togive 144 mg of a white solid (70%).

[0627] MS APCI+ve ^(m)/z 303/305 [(M+H)⁺].

[0628]¹H NMR 300 MHz (d₆-DMSO) 7.95 (3H, m), 7.78 (1H, d), 7.56 (1H, d),7.53 (1H, d), 7.34 (1H, dd), 5.36−5.30 (1H, m), 3.08−2.84 (2H, m),2.46−2.26 (2H, m).

EXAMPLE 56

[0629] 2-[3-Amino-1-(2-oxazolyl)propoxy]-4-chlorobenzonitrile oxalate

[0630] a) 3-Chloro-1-(2-oxazolyl)-1-propanone

[0631] To a solution of oxazole (2.93 g, 42.5 mmol) in tetrahydrofuran(150 ml) at −70° C. under a nitrogen atmosphere was added n-butyllithium(17 ml of a 2.5M solution in hexanes) dropwise and the solution stirredfor 20 minutes. Zinc chloride (84.9 ml of a 1M solution in diethylether) was added and the solution warmed to 0° C. over 45 minutes. Solidcuprous iodide (8.09 g, 42.5 mmol) was added and after 10 minutes,3-chloropropionyl chloride (8.38 ml, 87.8 mmol) was added. After 1 h,ethyl acetate and aqueous ammonium chloride solution were added. Theorganic layer was separated and washed sequentially with aqueousammonium chloride solution, water and brine. The solution was dried(sodium sulphate) and evaporated to yield 15.5 g of the crude product asa red oil. This mixture was used without further purification.

[0632]¹H NMR 300 MHz (CDCl₃) 7.86 (1H, s), 7.36 (1H, s), 3.93 (2H, t),3.57 (2H, m).

[0633] b) R-α-(2-Azidoethyl)-2-oxazolemethanol

[0634] (S)-2-Methyl-CBS-oxazaborolidine (0.72 ml of a 1M solution intoluene) was added to tetrahydrofuran (5 ml) under a nitrogen atmosphereand the solution cooled to −5° C. Borane-tetrahydrofuran complex (7.2 mlof a 1M solution in tetrahdrofuran) was added dropwise and the solutionstirred for 10 minutes. A solution of the crude product from Example56(a) (ca. 7.24 mmol) in tetrahydrofuran (7 ml) was added dropwise andthe reaction warmed slowly to 0° C. over 16 h. Methanol (20 ml) wascautiously added and the volatiles removed in vacuo. Two furthermethanol addition/solvent evaporation cycles were performed. The residuewas purified by flash chromatography using 10-40% ethylacetate/isohexane as eluent to give 724 mg of a colourless oil. This wastaken up into dimethylsulfoxide (5 ml), solid sodium azide (450 mg)added and the reaction heated at 65° C. for 16 h. After cooling to roomtemperature, water was added and the solution extracted with diethylether (3×). The combined organic extracts were dried (sodium sulphate)and the solvent removed in vacuo to yield 490 mg of the sub titlecompound as an orange oil that was used without further purification.

[0635]¹H NMR 300 MHz (CDCl₃) 7.65 (1H, s), 7.10 (1H, s), 4.97 (1H, dt),3.63−3.47 (2H, m), 3.05 (1H, bs), 2.28−2.07 (2H, m).

[0636] c) 2-[3-Amino-1-(2-oxazolyl)propoxy]-4-chlorobenzonitrile oxalate

[0637] To a solution of the product from Example 56(b) (160 mg) indimethylformamide (2 ml) was added sodium hydride (76 mg of a 60%dispersion in mineral oil) and the reaction stirred for 1 h. Solid4-chloro-2-fluoro-benzonitrile (296 mg) was added and the reactionstirred for 2 h. Water was added and the solution extracted with diethylether. The organic extract was separated, dried (sodium sulphate) andthe solvent removed in vacuo. The residue was taken up intetrahydrofuran (4 ml) and triphenylphosphine (283 mg) added. After 5minutes, water (1 ml) was added and the reaction stirred for 16 h.Further water (2 ml) was added and the reaction stirred at 55° C. for 3h and then 48 h at room temperature. The reaction was poured into ethylacetate/aqueous 1N sodium hydroxide. The organic extract was separated,dried (sodium sulphate) and the solvent removed in vacuo. Purificationby RP-HPLC afforded the free base of the title product (20 mg) as awhite solid. This was taken up in diethylether/dichloromethane (1:1) anda solution of oxalic acid (15 mg) in diethyl ether (1 ml) added. Theresulting solid was filtered off and dried in vacuo to yield 4 mg of thetitle product as a hydroscopic white solid.

[0638] MS APCI+ve ^(m)/z 278 [(M+H)⁺].

[0639]¹H NMR 400 MHz (d₄-MeOH) 7.87 (1H, s), 7.66 (1H, d), 7.34 (1H, s),7.22 (1H, d), 7.17 (1H, s), 3.21 (1H, m), 3.10 (1H, m), 2.73 (1H, ddd),2.46 (1H, ddd).

EXAMPLE 57

[0640] γ-(2,5-Dichlorophenoxy)-2-oxazolepropanamine oxalate

[0641] The title compound was prepared from the product from Example56(b) and 1,4-dichloro-2-fluoro-benzene using similar procedures toExample 56(c). Final purification was by recrystallisation(2-propanol/methanol/diethyl ether) to afford a beige solid.

[0642] MS APCI+ve ^(m)/z 287 [(M+H)⁺].

[0643]¹H NMR 400 MHz (d₄-MeOH) 7.96 (1H, s), 7.37 (1H, d), 7.23 (1H, s),7.18 (1H, m), 7.02 (1H, dd), 5.70 (1H, dd), 3.28 (2H, m), 2.59 (1H, m),2.47 (1H, m).

EXAMPLE 58

[0644]2-[[-3-Amino-1-(3-pyridinyl)propyl]oxy]-4-chloro-5-fluorobenzonitrileoxalate

[0645] a) [3-Oxo-3-(3-pyridinyl)propyl]carbamic acid,1,1-dimethylethylester

[0646] Isopropylmagnesium bromide (7.1 ml, 2M in tetrahydrofuran, 14.2mmol) was added to a solution of 3-bromopyridine (2.24 g, 14.2 mmol) intetrahydrofuran (15 ml) at 0° C. and stirred at 20° C. for 1 h. Asolution of 1,1-dimethylethyl [3-(methoxymethylamino)-3-oxopropylcarbamate (1.08 g, 4.65 mmol) in tetrahydrofuran (6 ml) was added andthe mixture was stirred for 18 h. The mixture was quenched withsaturated aqueous ammonium chloride and extracted with diethyl ether(three times) The combined organic extracts were dried (sodium sulphate)and evaporated to give an oil. Purification by chromatography on silicaeluting with petrol-acetone gave 568 mg (49%) of the sub-title compoundas a colourless oil.

[0647] MS APCI+ve ^(m)/z 251 [(M+H)⁺].

[0648] b) [3-Hydroxy-3-(3-pyridinyl)propyl]carbamic acid,1,1-dimethylethyl ester

[0649] Borane (3.0 ml, 1M in tetrahydrofuran) was added to a solution of(3aS)-tetrahydro-1-methyl-3,3-diphenyl-3H-pyrrolo[1,2-c][1,3,2]oxazaborole(0.22 ml, 1M in toluene) in tetrahydrofuran (5 ml) at 0° C. A solutionof the product from step (a) (1.13 g, 4.52 mmol) in tetrahydrofuran (3ml) was added over 30 minutes and then stirred at 20° C. for 24 h.Methanol was added and the solution was evaporated and methanol (15 ml)and 2M hydrochloric acid (5 ml) were added and stirred for 45 minutes.Aqueous potassium carbonate and di-tert-butyldicarbonate (250 mg) wereadded and the mixture was extracted with ethyl acetate (2×) anddichloromethane (4×). ) The organic extracts were dried (sodiumsulphate), evaporated and purified by chromatography on silica elutingwith dichloromethane—methanol to give 928 mg (73%) of the sub-titlecompound as a colourless oil.

[0650] MS APCI+ve ^(m)/z 253 [(M+H)⁺].

[0651] c)[(3-(5-chloro-2-cyano-4-fluorophenoxy)-3-(3-pyridinyl)propyl]carbamicacid, 1,1 dimethylethyl ester

[0652] Sodium hydride (141 mg, 60% dispersion in oil) was added to asolution of the product from step (b) (785 mg, 2.96 mmol) and4-chloro-2,5-difluorobenzonitrile (546 mg, 3.75 mmol) in tetrahydrofuran(9 ml) and the resultant suspension was stirred for 0.5 h. The mixturewas quenched with saturated aqueous ammonium chloride, basified to pH 8and extracted with ethyl acetate (three times). The combined organicextracts were dried (sodium sulphate), evaporated and purified bychromatography on silica eluting with petrol—acetone to give 1.05 g(88%) of the sub-title compound as a colourless oil.

[0653] MS APCI+ve ^(m)/z 406 [(M+H)⁺].

[0654] d)2-[[-3-Amino-1-(3-pyridinyl)propyl]oxy]-4-chloro-5-fluorobenzonitrileoxalate

[0655] A solution of the product from step (c) (227 mg, 0.56 mmol) in 4MHCl in dioxan (4 ml) was stirred for 0.5 h. Aqueous potassium carbonatewas added and the mixture was extracted with dichloromethane. Theorganic extracts were dried (sodium sulphate), evaporated and purifiedby chromatography on silica eluting with dichloromethane—3M ammonia inmethanol to give a pale yellow gum (167 mg). To a solution of this aminein isopropanol (3 ml) was added a solution of oxalic acid (23 mg) in hotmethanol (0.3 ml). The crystals that formed on cooling were collectedand dried to afford 180 mg (100%) of the title compound as a whitesolid.

[0656] MS APCI+ve ^(m)/z 306 [(M+H)⁺].

[0657]¹H NMR 400 MHz (d₆-DMSO) 8.66 (d, 1H), 8.56 (dd, 1H), 8.02 (d,1H), 7.82 (dt, 1H), 7.52 (d, 1H), 7.46 (dd, 1H), 6.42 (s, 2H), 5.92 (dd,1H), 2.89 (t, 2H), 2.37−2.27 (m, 1H), 2.21−2.10 (m, 1H).

EXAMPLE 59

[0658]4-Chloro-5-fluoro-2-[3-(methylamino)-1-(3-pyridinyl)propoxy]benzonitrileoxalate

[0659] a)[(3-(5-Chloro-2-cyano-4-fluorophenoxy)-3-(3-pyridinyl)propyl]carbamicacid 1,1 dimethylethyl ester

[0660] Sodium hydride (34.2 mg, 60% dispersion in oil, 0.86 mmol) wasadded to a solution of the product from Example 58(c) (219 mg, 0.54mmol) and methyl iodide (0.2 ml, 3.2 mmol) in tetrahydrofuran (4 ml) andstirred for 3 h. Aqueous ammonium chloride was added and the mixture wasextracted with dichloromethane (three times). The combined organicextracts were dried (sodium sulphate), evaporated and purified bychromatography on silica eluting; with petrol—acetone to give thesub-title compound as a colourless oil (157 mg, 69%).

[0661] MS APCI+ve ^(m)/z 420 [(M+H)⁺].

[0662] b)4-Chloro-5-fluoro-2-[3-(methylamino)-1-(3-pyridinyl)propoxy]benzonitrileoxalate

[0663] The title compound was prepared from the product of Example 59(a)by the method of Example 58(d).

[0664] MS APCI+ve ^(m)/z 320 [(M+H)⁺].

[0665]¹H NMR 400 MHz (d₆-DMSO) 8.67 (d, 1H), 8.57 (d, 1H), 8.03 (d, 1H),7.83 (d, 1H), 7.54 (d, 1H), 7.47 (dd, 1H), 5.88 (t, 1H, 3.11−2.95 (m,2H), 2.59 (s, 3), 2.45−2.32 (m, 1H), 2.30−2.19(m, 1H).

EXAMPLE 60

[0666] γ-[2-Chloro-5-(trifluoromethyl)phenoxy]-3-pyridinepropanamineoxalate

[0667] a)[(3-(2-Chloro-5-trifluoromethylphenoxy)-3-(3-pyridinyl)propyl]-carbamicacid 1,1-dimethylethyl ester

[0668] Diethyl azodicarboxylate (0.71 ml, 4.47 mmol) was added to asolution of [3-hydroxy-3-(3-pyridinyl)propyl]carbamic acid1,1-dimethylethyl ester (Example 58(b)) (291 mg, 1.15 mmol),2-chloro-5-trifluoromethylphenol (232 mg, 1.18 mmol) andtriphenylphosphine (455 mg, 1.73 mmol) in tetrahydrofuran (6 ml) at 0°C. and stirred at 20° C. for 18 h. The reaction was concentrated invacuo and the residue purified by chromatography on silica, eluting withpetrol—diethyl ether to afford the sub-title compound (394 mg, 79%).

[0669] MS APCI+ve ^(m)/z 431 [(M+H)⁺].

[0670] b) γ-[2-Chloro-5-(trifluoromethyl)phenoxy]-3-pyridinepropanamineoxalate

[0671] The title compound was prepared by the method of Example 58(d)using the product of Example 60(a).

[0672] MS APCI+ve ^(m)/z 331 [(M+H)⁺].

[0673]¹H NMR 300 MHz (d₆-DMSO) δ8.64 (d, 1H), 8.54 (dd, 1H), 7.99 (s,2H), 7.81 (dt, 1H), 7.69 (d, 1H), 7.44 (dd, 1H), 7.36−7.28 (m, 2H), 5.93(dd, 1H), 3.02−2.91 (m, 2H), 2.42−2.12 (m, 2H).

EXAMPLE 61

[0674]2-[3-Amino-1-(6-methoxy-2-pyridinyl)propoxy]-4-chloro-5-fluorobenzonitrileoxalate

[0675] a) [3-(6-Methoxy-2-pyridinyl)-3-oxopropyl]carbamic acid1,1-dimethylethyl ester

[0676] Butyl lithium (2.5M solution in hexanes, 1.4 ml) was added to asolution of 6-bromo-2-methoxypyridine (690 mg, 4.0 mmol) intetrahydrofuran (4 ml) at −78° C. and stirred for 1 h. A solution of[3-(methoxymethylamino)-3-oxopropyl carbamic acid 1,1-dimethylethylester (344 mg, 1.42 mmol) in tetrahydrofuran (3 ml) was added and themixture was warmed to 0° C. over 3 h. The mixture was quenched withsaturated aqueous ammonium chloride and extracted with ethyl acetate(three times) The combined organic extracts were dried (sodiumsulphate), evaporated and purified by chromatography on silica elutingwith petrol-acetone to give the sub-title compound as a colourless oil(291 mg, 73%).

[0677] MS APCI+ve ^(m)/z 281 [(M+H)⁺].

[0678] b) 1[3-Hydroxy-3-(6-methoxy-2-pyridinyl)-propyl]carbamic acid1,1-dimethylethyl ester

[0679] A mixture of the product from Example 61(a) (489 mg, 1.75 mmol)and sodium tetrahydroborate (133 mg, 3.52 mmol) in tetrahydrofuran (4ml) was stirred for 5 h. 2M Hydrochloric acid was added and the mixturewas extracted with ethyl acetate (three times). The combined organicextracts were dried (sodium sulphate), evaporated and purified bychromatography on silica eluting with petrol-ether to give the sub-titlecompound as a colourless oil (446 mg, 90%).

[0680] MS APCI+ve ^(m)/z 283 [(M+H)⁺].

[0681] c)[(3-(5-Chloro-2-cyano-4-fluorophenoxy)-3-(6-methoxy-2-pyridinyl)-propyl]-carbamicacid 1,1-dimethylethyl ester

[0682] The sub-title compound was prepared by the method of Example58(c) using [3-hydroxy-3-(6-methoxy-2-pyridinyl)propyl]carbamic acid1,1-dimethylethyl ester (Example 61(b)) and4-chloro-2,5-difluorobenzonitrile.

[0683] MS APCI+ve ^(m)/z 436 [(M+H)⁺].

[0684] d)2-[3-Amino-1-(6-methoxy-2-pyridinyl)propoxyl-4-chloro-5-fluorobenzamideoxalate

[0685] The title compound was prepared from the product of Example 61(c)by the method of Example 58(d).

[0686] MS APCI+ve ^(m)/z 336 [(M+H)⁺].

[0687]¹H NMR 300 MHz (d₆-DMSO) 8.05 (d, 1H), 7.76 (t, 1H), 7.48 (d, 1H),7.04 (d, 1H), 6.80 (d, 1H), 5.71 (t, 1H), 3.85 (s, 3H), 3.04−2.95 (m,2H), 2.39−2.25 (m, 2H).

EXAMPLE 62

[0688]2-[[(1R)-3-Amino-1-(5-methyl-3-isoxazolyl)propyl]oxy]-4-chloro-5-fluoro-benzonitrilefumarate

[0689] 5-Methylisoxazole-3-carboxylic acid was converted into the titleproduct by the procedures described for Example 89 steps (a) to (c) andExample 93 steps (a) to (c) to afford a solid.

[0690] MS APCI+ve ^(m)/z 310 [(M+H)⁺].

[0691]¹H NMR 300 MHz (d₆-DMSO) 8.04 (1H, d), 7.58 (1H, d), 6.40 (2H, s),6.34 (1H, s), 5.99−5.91 (1H, m), 2.94 (2H, t), 2.40 (3H, s), 2.38−2.29(1H, m), 2.26−2.15 (1H, m).

EXAMPLE 63

[0692]2-[3-Amino-1-(1,6-dihydro-6-oxo-2-pyridinyl)propoxy]-4-chloro-5-fluorobenzonitrileoxalate

[0693] A solution of the product from Example 61(d) (313 mg, 0.932 mmol)in 62% aqueous hydrogen bromide (2 ml) was heated at 70° C. for 5.5 h.Aqueous potassium carbonate was added and the mixture was extracted withdichloromethane. The organic extracts were dried (sodium sulphate),evaporated and purified by chromatography on silica eluting withdichloromethane—7M ammonia in methanol and then methanol to give:—

[0694]2-[3-amino-1-(6-methoxy-2-pyridinyl)propoxy]-4-chloro-5-fluorobenzamide,33.8 mg. The oxalate salt was prepared by the method of Example 58(d) togive a solid (31.7 mg). MS APCI+ve ^(m)/z 354 [(M+H)⁺]. ¹H NMR 400 MHz(d₆-DMSO) 8.11−7.88 (m, 4H), 7.73 (ddd, 1H), 7.65 (d, 1H), 7.38 (d, 1H),7.07 (d, 1H), 6.78 (d, 1H), 5.76−5.70 (m, 1H), 3.85 (s, 3H), 3.04−2.89(m, 2H), 2.38−2.20 (m, 2H);

[0695] followed by2-[3-amino-1-(1,6-dihydro-6-oxo-2-pyridinyl)propoxy]-4-chloro-5-fluorobenzonitrile,9.5 mg, which was converted into the oxalate salt as in Example 58(d) togive a solid (5.3 mg).

[0696] MS APCI+ve ^(m)/z 322 [(M+H)⁺].

[0697]¹H NMR 400 MHz (d₆-DMSO) 8.08 (d, 1H), 7.99−7.76 (m, 2H), 7.53 (t,1H), 7.34 (d, 1H), 6.45 (d, 2H), 5.48 (s, 1H), 2.94 (s, 2H), 2.39−2.17(m, 2H).

EXAMPLE 64

[0698] (R)-γ-[2-Chloro-5-(trifluoromethyl)phenoxy]-2-pyridinepropanaminedihydrochloride

[0699] a) [3-Oxo-3-(2-pyridinyl)propyl]carbamic acid 1,1-dimethylethylester

[0700] 2-Bromopyridine (3.16 g) in dry ether (50 ml) was cooled to −60°C. under a nitrogen atmosphere. N-Butyllithium (2.5M solution inhexanes, 8.5 ml) was added dropwise and stirring at −60° C. continuedfor a further 15 minutes. A solution of 1,1-dimethylethyl(methoxymethylamino)-3-oxopropyl]carbamate (2.32 g) in ether (20 ml) wasadded dropwise and the reaction stirred at −40° C. for 1 h and then at0° C. for 0.5 h. The reaction was quenched with saturated ammoniumchloride and extracted with ethyl acetate. The organic extract waswashed with water, then brine, dried over magnesium sulphate andevaporated to an oil which was passed down a silica gel column elutedwith hexane:ethyl aceate (4:1) to afford the product as a pale yellowoil (1.4 g).

[0701] MS APCI+ve ^(m)/z 251 [(M+H)⁺].

[0702]¹H NMR 300 MHz (CDCl₃) 8.68 (1H, dt), 8.03 (1H, d), 7.84 (1H, td),7.48 (1H, ddd), 5.10 (1H, s), 3.56 (2H, q), 3.43 (2H, t), 1.43 (9H, s).

[0703] b) [(3S)-3-Hydroxy-3-(2-pyridinyl)propyl]carbamic acid1,1-dimethylethyl ester

[0704] The product of step (a) (0.6 g) was reduced by the proceduredescribed in Example 68(a) to afford the product as a clear oil (0.24g).

[0705]¹H NMR 400 MHz (CDCl₃) 8.53 (1H, d), 7.70 (1H, dd), 7.36 (1H, d),7.20 (1H, dd), 5.04 (1H, s), 4.82 (1H, dt), 4.65 (1H, s), 3.45 (1H, m),3.33−3.17 (1H, m), 2.09 (1H, dd), 1.84−1.71 (1H, m), 1.44 (9H, s).

[0706] c)(R)-3-[2-Chloro-5-(trifluoromethyl)phenoxy]-3-(2-pyridinyl)propyl]carbamicacid, 1,1-dimethylethyl ester

[0707] The product of step (b) (0.24 g) and2-chloro-4-trifluoromethylphenol were subjected to the proceduredescribed in Example 8(a) to afford the product as an oil (0.3 g).

[0708] MS APCI+ve ^(m)/z 431 [(M+H)⁺].

[0709]¹H NMR 400 MHz (CDCl₃) 8.60 (1H, dd), 7.67 (1H, td), 7.47 (1H, d),7.37 (1H, d), 7.22 (1H, ddd), 7.11 (1H, dd), 6.95 (1H, d), 5.44 (1H,dd), 5.15 (1H, s), 3.45 (1H, dq), 3.30 (1H, dt), 2.38−2.20 (2H, m), 1.40(9H, s).

[0710] d)(R)-γ-[2-Chloro-5-(trifluoromethyl)phenoxy]-2-pyridinepropanaminedihydrochloride

[0711] The product of step (c) (0.3 g) was subjected to the proceduredescribed in Example 88(b) to afford the product as a white solid (0.25g).

[0712] MS APCI+ve ^(m)/z 331 [(M+H)⁺].

[0713]¹H NMR 400 MHz (d₆-DMSO) 8.63 (1H, dd), 8.11 (3H, s), 7.88 (1H,td), 7.71 (1H, d), 7.47 (1H, d), 7.40 (1H, ddd), 7.30 (1H, d), 7.24 (1H,d), 5.84 (1H, dd), 3.01 (2H, d), 2.43−2.23 (2H, m).

EXAMPLE 65

[0714] 2-[3-Amino-1-(6-bromo-3-pyridinyl)propoxy]-4-chlorobenzonitrileoxalate

[0715] a) [3-(6-Bromo-3-pyridinyl)-3-oxopropyl] carbamic acid,1,1-dimethylethyl ester

[0716] The sub-title compound was prepared from 2,5-dibromopyridine and[3-(mcthoxymethylamino)-3-oxopropyl carbamic acid, 1,1-dimethylethylester by the method of Example 58(a).

[0717]¹H NMR 300 MHz (CDCl₃) 8.90 (1H, d), 8.07 (1H, dd), 7.62 (1H, dd),5.07 (1H, s), 3.53 (1H, q), 3.50 (1H, q), 3.19 (2H, t), 1.43 (9H, s).

[0718] b) [3-(6-Bromo-3-pyridinyl)-3-hydroxypropyl]carbamic acid1,1-dimethylethyl ester

[0719] A mixture of product from Example 65(a) (645 mg, 1.96 mmol) andsodium tetrahydroborate (115 mg, 3.04 mmol) in tetrahydrofuran (5 ml)was stirred for 18 h. 2M hydrochloric acid was added and the mixture wasextracted with ethyl acetate (three times). The combined organicextracts were dried (magnesium sulphate), evaporated and purified bychromatography on silica eluting with diethyl ether to give thesub-title compound as a colourless oil (6.60 g).

[0720]¹H NMR 300 MHz (CDCl₃) 8.33 (1H, d), 7.63 (1H, dd), 7.46 (1H, d),4.95−4.86 (1H, m), 4.78−4.69 (1H, m), 4.33−4.27 (1H, m), 3.68−3.51 (1H,m), 3.22−3.09 (1H, m), 1.89−1.66 (2H, m), 1.46 (9H, s).

[0721] c)[3-(6-Bromo-3-pyridinyl)-3-(5-chloro-2-cyanophenoxy)propyl]carbamic acid1,1-dimethylethyl ester

[0722] The sub-title compound was prepared from the product of Example65(b) and 4-chloro-2-hydroxybenzonitrile by the method of Example 60(a).

[0723]¹H NMR 300 MHz (CDCl₃) 8.40 (1H, d), 7.65 (1H, dd), 7.55−7.41 (1H,m), 7.33 (1H, d), 7.06−6.93 (1H, m), 6.80 (1H, d), 5.38 (1H, dd), 4.84(1H, s), 3.45−3.28 (2H, m), 2.36−2.03 (2H, m), 1.44 (9H, s).

[0724] d)2-[3-Amino-1-(6-bromo-3-pyridinyl)propoxy]-4-chlorobenzonitrile oxalate

[0725] The title compound was prepared from the product of Example 65(c)by the method of Example 58(d).

[0726] MS APCI+ve ^(m)/z 366 [(M+H)⁺].

[0727]¹H NMR 300 MHz (d₆-DMSO) 8.50 (s, 1H), 7.85−7.70 (m, 3H), 7.31 (s,1H), 7.21 (dd, 1H, 5.96−5.88 (m, 1H), 2.94−2.86 (m, 2H), 2.39−2.07 (m,2H).

EXAMPLE 66

[0728] 2-[[3-Amino-1-(5-isoxazolyl)propyl]oxy]-4-chlorobenzonitrileoxalate

[0729] a) N-Methoxy-N-methyl-5-isoxazolecarboxamide

[0730] A solution of isoxazole 5-carboxylic acid (2.81 g),N-methoxy-N-methylamine hydrochloride (2.49 g), EDCI (4.96 g),dimethylaminopyridine (3.15 g) and 4-methylmorpholine (2.8 ml) indichloromethane (20 ml) was stirred for 18 h. 2M Hydrochloric acid wasadded and the mixture was extracted with dichloromethane (three times).The organic layers were washed with aqueous sodium hydrogen carbonateand then brine, combined, dried (magnesium sulphate), evaporated andpurified by chromatography on silica eluting with petrol-ether to givethe sub-title compound as a colourless oil (2.94 g, 76%).

[0731]¹H NMR 300 MHz (CDCl₃) 8.35 (1H, d), 6.89 (1H, d), 3.83 (3H, s),3.39 (3H, s).

[0732] b) 3-Chloro-1-(5-isoxazolyl)-1-propanone

[0733] Vinyl magnesium bromide (20 ml, 1M in tetrahydrofuran) was addedto a solution of the product from Example 66(a) (2.59 g, 16.6 mmol) intetrahydrofuran (35 ml) at −78° C. and warmed to 0° C. over 2.5 h. Aftercooling to −50° C., the mixture was slowly poured into excess iced 2Mhydrochloric acid. The mixture was extracted with ether (five times).The organic extracts were dried (magnesium sulphate) and evaporated togive a brown oil. 1M Hydrogen chloride in diethyl ether (20 ml) wasadded and stirred for 40 minutes. The solvent was removed its vacuto togive the sub-title compound (2.0 g, 75%).

[0734]¹H NMR 300 MHz (CDCl₃) 8.39 (1H, s), 6.96 (1H, s), 3.91 (2H, t),3.49 (2H, t).

[0735] c) α-(2-Chloroethyl)-5-isoxazolemethanol

[0736] Borane (4.2 ml, 1M in tetrahydrofuran) was added to a solution of(3αS)-tetrahydro-1-methyl-3,3-diphenyl-3H-pyrrolo[1,2-c][1,3,2]oxazaborole (0.06 ml, 1M in toluene) in tetrahydrofuran (5ml) at 0° C. A solution of the product from Example 66(b) (998 mg, 6.25mmol) in tetrahydrofuran (5 ml) was added slowly and then stirred at 20°C. for 4 h. Methanol was added and the solution was evaporated and theresidue azeotroped with methanol. Purification by chromatography onsilica eluting with petrol-ether gave the sub-title compound as acolourless oil (562 mg, 56%).

[0737] MS APCI+ve ^(m)/z 162 [(M+H)⁺].

[0738] d) 4-Chloro-2-[3-chloro-1-(5-isoxazolyl)propoxy]-benzonitrile

[0739] Prepared by the method of Example 8(a) usingα-(2-chloroethyl)-5-isoxazolemethanol and4-chloro-2-hydroxybenzonitrile.

[0740]¹H NMR 300 MHz (CDCl₃) 8.26 (1H, d), 7.52 (1H, dd), 7.09 (1H, dt),7.02 (1H, s), 6.36 (1H, t), 5.82−5.74 (1H, m), 3.95−3.84 (1H, m),3.81−3.70 (1H, m), 2.75−2.61 (1H, m), 2.54−2.40 (1H, m).

[0741] e) 2-[[3-Amino-1-(5-isoxazolyl)propyl]oxy]-4-chlorobenzonitrileoxalate

[0742] A solution of the product from Example 66(d) (100 mg, 0.34 mmol)and sodium azide (34 mg,0.52 mmol) in DMSO (0.8 ml) was stirred for 3days. Triphenylphosphine (88 mg, 0.34 mmol), tetrahydrofuran (2 ml) andwater (0.5 ml) were added and the solution was stirred for 2 days.Purification by chromatography on silica eluting with dichloromethane—7Mammonia in methanol gave a pale yellow gum (27 mg). To a solution ofthis amine in isopropanol (3 ml) was added a solution of oxalic acid (9mg) in methanol (0.3 ml). The crystals that formed on cooling werecollected and dried to afford the title compound as a white solid (91mg, 97%).

[0743] MS APCI+ve ^(m)/z 278 [(M+H)⁺].

[0744]¹H NMR 300 MHz (d₆-DMSO) 8.61 (1H, d), 7.82 (1H, d), 7.51 (1H, d),7.25 (1H, dd), 6.68 (1H, d), 6.15 (1H, t), 5.46 (3H, s), 2.88 (2H, t),2.42−2.21 (2H, m).

EXAMPLE 67

[0745]4-Chloro-2-[3-[(2-hydroxyethyl)amino]-1-(5-isoxazolyl)propoxy]benzonitrileoxalate

[0746] a) 4-Chloro-2-[3-iodo-1-(5-isoxazolyl)propoxy]benzonitrile

[0747] A solution of the chloride from Example 66(d) (106 mg, 0.356mmol) and sodium iodide (1 g) in acetone (10 ml) was stirred at 20° C.for 2 days and at 55° C. for 1 day. The solvent was removed in vacuo,water added and the mixture was extracted with dichloromethane (threetimes). The organic layers dried (sodium sulphate), evaporated to givethe sub-title compound (159mg, 100%).

[0748]¹H NMR 300 MHz (CDCl₃) 8.26 (1H, d), 7.53 (1H, d), 7.08 (1H, dd),7.03 (1H, s), 6.35 (1H, s), 5.66 (1H, dd), 3.53−3.30 (2H, m), 2.72−2.04(2H, m).

[0749] b)4-Chloro-2-[3-[(2-hydroxyethyl)amino]-1-(5-isoxazolyl)propoxy]benzonitrileoxalate

[0750] A solution of4-chloro-2-[3-iodo-1-(5-isoxazolyl)propoxy]benzonitrile (159 mg, 0.41mmol) and ethanolamine (0.2 ml) in tetrahydrofuran (2 ml) was stirredfor 2 days. Water was added and the mixture was extracted withdichloromethane The combined organic extracts were dried (sodiumsulphate), evaporated and purified by chromatography on silica elutingwith dichloromethane—7M ammonia in methanol to give an orange gum (40mg). The oxalate salt was prepared as in Example 58(d) to afford thetitle compound as a white solid (40 mg, 30%).

[0751] MS APCI+ve ^(m)/z 322 [(M+H)⁺].

[0752]¹H NMR 400 MHz (d₆-DMSO) 8.63 (d, 1H), 7.83 (d, 1H), 7.52 (d, 1H),7.27 (dd, 1H), 6.69 (d, 1H), 6.17 (t, 1H), 3.94 (s, 2H), 3.65 (t, 4H),3.10 (t, 1H), 3.04 (t, 1H), 2.48−2.43 (m, 2H).

EXAMPLE 68

[0753] (R)-γ-(2,5-Dichlorophenoxy)-5-isoxazolepropanamine oxalate

[0754] a) (S)-α-(2-Chloroethyl)-5-isoxazolemethanol

[0755] Borane (18 ml, 1M in tetrahydrofuran) was added to a solution of(3aR)-tetrahydro-1-methyl-3,3-diphenyl-3H-pyrrolo[1,2-c][1,3,2]oxazaborole(1.3 ml, 1M in toluene) in tetrahydrofuran (10 ml) at −10° C. A solutionof 3-chloro-1-(3-isoxazolyl)-1-propanone (Example 66(b)) (6 g, 37.6mmol) in tetrahydrofuran (12 ml) was added slowly and then stirred at−10° C. to 20° C. for 18 h. Methanol was added and the solution wasevaporated and the residue azeotroped with methanol. Purification bychromatography on silica eluting with petrol-ether gave the sub-titlecompound as a colourless oil (774 mg, 13%).

[0756] MS APCI+ve ^(m)/z 162 [(M+H)⁺].

[0757] b) (S)-α-(2-Azidoethyl)-5-isoxazolemethanol

[0758] A solution of the product from Example 68(a) (767 mg, 4.76 mmol)and sodium azide (342 mg, 5.26 mmol ) in DMSO (8 ml) was heated at 65°C. for 18 h. Water was added and the mixture was extracted with ethylacetate (three times). The combined organic extracts were dried(magnesium sulphate), evaporated and purified by chromatography onsilica eluting with petrol—diethyl ether to give the sub-title compoundas a colourless oil (454 mg, 57%).

[0759]¹H NMR 300 MHz (CDCl₃) 8.22 (1H, d), 6.26 (1H, t), 5.12−5.03 (1H,m), 3.65−3.46 (2H, m), 2.54 (1H, d), 2.18−2.05 (2H, m).

[0760] c) (R)-γ-(2.5-Dichlorophenoxy)-5-isoxazolepropanamine oxalate

[0761] Diethyl azodicarboxylate (0.23 ml, 1.46 mmol) was added to asolution of triphenylphosphine (355 mg, 1.35 mmol) in tetrahydrofuran (3ml) at 0° C. After 10 minutes a solution of the product from Example68(b) (151 mg, 0.90 mmol) and 2,5-dichlorophenol (164 mg, 1.0 mmol) intetrahydrofuran (3 ml) were added and stirred at 20° C. for 3 h.Triphenylphosphine (268 mg, 1.02 mmol) and water (1 ml) were added andstirred for 2.5 days. The reaction was concentrated in vacuo and theresidue purified by chromatography on silica, eluting withdichloromethane—7M ammonia in methanol to give a pale yellow gum (91mg). To a solution of this amine in isopropanol (3 ml) was added asolution of oxalic acid (26 mg) in methanol (1 ml). The crystals thatformed on cooling were collected and dried to afford the title compoundas a white solid (37 mg, 14%).

[0762] MS APCI+ve ^(m)/z 287 [(M+H)⁺].

[0763]¹H NMR 300 MHz (d₆-DMSO) 8.61 (1H, d), 7.50 (1H, d), 7.34 (1H, d),7.11 (1H, d of d), 6.62 (1H, d), 6.02 (1H, d), 2.98 (2H, t), 2.44−2.24(2H, m).

EXAMPLE 69

[0764] (R)-γ-(2,5-Dichlorophenoxy)-N-methyl-benzenepropanamine fumarate

[0765] Using [(3S)-3-hydroxy-3-phenylpropyl]methylcarbamic acid1,1-dimethylethyl ester (266 mg, 1.0 mmol) and 9,5-dichlorophenol (163mg, 1.0 mmol), the title compound was prepared using the proceduredescribed in Example 2(b), with a final conversion into a fumarate salt.

[0766] MS APCI+ve ^(m)/z 310 [(M+H)⁺].

[0767]¹H NMR 300 MHz (d₆-DMSO) 7.45−7.28 (6H, m), 7.08 (1H, d),6.98−6.95 (1H, dd), 6.45 (2H, s), 5.75−5.71 (1H, m), 2.95−2.90 (2H, t),2.50 (3H, s), 2.34−2.08 (2H, m).

EXAMPLE 70

[0768](R)-γ-[2-Chloro-5-(trifluoromethyl)phenoxy]-N-methyl-benzenepropanaminefumarate

[0769] Using 1,1-dimethylethylester[(3S)-3-hydroxy-3-phenylpropyl]methylcarbamic acid (281 mg, 1.06 mmol)and 4-chloro-3-hydroxybenzotrifluoride (208 mg, 1.06 mmol), the titlecompound was prepared using the procedure described in Example 2(b),with a final conversion into a fumarate salt.

[0770] MS APCI+ve ^(m)/z 344 [(M+H)⁺].

[0771]¹H NMR 300 MHz (d₆-DMSO) 7.67−7.64 (1H,dd), 7.44−7.23 (7H,m), 6.44(2H,s), 5.86−5.82 (1H,m), 2.94 (2H,t), 2.50 (3H,s), 2.38−2.12 (2H,m).

EXAMPLE 71

[0772]4-Chloro-2-[[(1R)-3-(methylamino)-1-(2-thienyl)propyl]oxy]benzonitrileoxalate

[0773] a)4-Chloro-2-[[(1R)-3-chloro-1-(2-thienyl)propyl]oxy]benzonitrile

[0774] Using 4-chloro-2-hydroxybenzonitrile (303 mg, 1.97 mmol) and(S)-α-(2-chloroethyl) thiophenemethanol (349 mg, 1.97 mmol), and theprocedure described in Example 5(a), the title compound was prepared asa white crystalline solid (373 mg, 61%).

[0775]¹H NMR300 MHz (CDCl₃) 7.48−7.45 (1H,d), 7.33−7.31 (1H,dd),7.14−7.13 (1H,m), 7.03−6.97 (3H,m), 5.82−5.77 (1H,q), 3.91−3.83 (1H,m),3.67−3.59 (1H,m), 2.70−2.63 (1H,m), 2.42−2.33 (1H,m).

[0776] b) 4-Chloro-2-[[(1R)-3-iodo-1-(2-thienyl)propyl]oxy]benzonitrile

[0777] The product of step (a) (368 mg, 1.18 mmol) was converted intothe title compound using the procedure described in Example 5(b), givinga pale brown oil (408 mg, 86%). The product was used directly in thenext step.

[0778] c)4-Chloro-2-[[(1R)-3-(methylamino)-1-(2-thienyl)propyl]oxy]benzonitrileoxalate

[0779] The product of step (b) (400 mg, 0.99 mmol) was used to preparethe title compound by the procedure described in Example 5(c) exceptthat the oxalate salt was prepared (135 mg, 34%).

[0780] MS APCI+ve ^(m)/z 307 [(M+H)⁺].

[0781]¹H NMR 400 MHz (d₆-DMSO) 7.79−7.77 (1H,d), 7.58−7.56 (1H,d),7.47−7.46 (1H, 7.27−7.26 (1H,m), 7.20 −7.18 (1H,dd), 7.05−7.03 (1H,m),6.17−6.14 (1H,t), 3.09−2.94 (2H,m), 2.59 (3H,s), 2.50−2.39 (1H,m),2.33−2.22 (1H,m).

EXAMPLE 72

[0782]2-[[(1R)-3-Amino-1-(3-furanyl)propyl]oxy]-4-chloro-5-fluorobenzonitrilefumarate

[0783] a) [3-(3-Furanyl)-3-oxopropyl]-carbamic acid 1,1-dimethylethylester

[0784] 3-Bromofuran (5.88 g, 40 mmol) was dissolved in anhydroustetrahydrofuran (60 ml) and the solution cooled to −78° C.n-Butyllithium (2.29M, 17.5 ml, 40 mmol) was added dropwise and thesolution stirred for 1 h at −78° C.[3-(Methoxymethylamino)-3-oxopropyl]carbamic acid, 1,1-dimethylethylester as a solution in tetrahydrofuran (40 ml) was added dropwise over 1h. The solution was stirred overnight whilst allowing to warm to roomtemperature. Aqueous saturated ammonium chloride solution (30 ml) wasadded and the mixture extracted with ethyl acetate (3×70 ml). Thecombined organic extracts were washed with water (3×30 ml), dried(sodium sulphate) and evaporated in vacuo. The residue waschromatographed on flash silica, eluting with hexane:ethyl acetate(7:3), to afford the title compound as a pale yellow solid (3.03 g,63%).

[0785]¹H NMR 300 MHz CDCl₃ 8.05 (1H, d), 7.40-7.50 (1H, m), 6.72-6.82(1H, m), 5.07 (1H, s), 3.41-3.60 (2H, m), 2.90-3.09 (2H, m), 1.43 (9H,s).

[0786] b) [(3R)-3-(3-Furanyl)-3-hydroxypropyl]carbamic acid1,1-dimethylethyl ester

[0787] (S)-2-Methyl-CBS-oxazaborolidine (1M in toluene, 0.84 ml, 0.836mmol) was added to anhydrous tetrahydrofuran (50 ml) and the solutioncooled to 0° C. Borane:tetrahydrofuran complex (1M, 5.02 ml, 5.02 mmol)was then added dropwise, keeping the temperature at 0° C. The mixturewas stirred for 15 minutes then added the product of step (a) (2.0 g,8.36 mmol) as a solution in tetrahydrofuran (50 ml), dropwise over 1 hkeeping the temperature at 0° C. Stirred overnight whilst allowing towarm to room temperature. The reaction was quenched with methanol (5 ml)and stirred for a half hour. The solvent was removed in vacuo andanother aliquot of methanol (20 ml) added. The solvent was removed invacuo and the residue chromatographed on flash silica, eluting withhexane:ethyl acetate (1:1), to give the title compound as a colourlessoil (1.685 g, 84%).

[0788]¹H NMR 300 MHz (CDCl₃) 7.35-7.43 (2H, m), 6.40 (1H, t), 4.85 (1H,s), 4.69-4.77 (1H, m), 3.41-3.60 (1H, m), 3.09-3.30 (2H, m), 1.80-1.92(2H, m), 1.51 (9H, s).

[0789] c)[(3R)-3-(5-Chloro-2-cyano-4-fluorophenoxy)-3-(3-furanyl)propyl]-carbamicacid 1,1-dimethylethyl ester

[0790] The product of step (b) (277 mg, 1.15 mmol) and4-chloro-2,5-difluorobenzonitrile (199 mg, 1.15 mmol) were dissolved indimethylformamide (10 ml) and sodium hydride (60%, 48 mg, 1.2 mmol)added in one portion. The reaction was stirred for 2 h at roomtemperature then quenched with aqueous saturated ammonium chloridesolution (30 ml) and extracted with ethyl acetate (3×60 ml). Thecombined organic extracts were washed with water (3×20 ml), dried(sodium sulphate) and evaporated iii vacuo. The residue waschromatographed on flash silica, eluting with hexane:ethyl acetate(3:1), to give the title compound as a white crystalline solid (330 mg,73%).

[0791]¹H NMR 300 MHz (CDCl₃) 7.39-7.51 (2H, m), 7.36 (1H, s), 7.05 (1H,d), 6.43 (1H, t), 5.27-5.36 (1H, m), 5.19 (1H,s), 3.18-3.43 (2H, m),2.20-2.33 (1H, m), 2.02-2.13 (1H, m), 1.49 (9H, s).

[0792] d)2-[[(1R)-3-Amino-1-(3-furanyl)propyl]oxy]-4-chloro-5-fluorobenzonitrilefumarate

[0793] The product from step (c) (150 mg, 0.3 mmol) was dissolved in 4MHCl in dioxan (10 ml) and stirred at room temperature for 10 minutes.The reaction was placed in an ice-bath and aqueous saturated sodiumbicarbonate solution (30 ml) added cautiously. The mixture wa extractedwith ethyl acetate (3×50 ml) and the combined extracts were washed withwater (20 ml), dried (sodium sulphate) and evaporated in vacuo. Theresidue was chromatographed on flash silica, eluting with 5% 7N ammoniain methanol in dichloromethane. The product was dissolved in methanol (5ml) and treated with one equivalent of fumaric acid. Stirred for 10minutes then removed the solvent in vacuo and triturated the solidresidue with a little ethyl acetate. The white solid was filtered offand dried to give the title compound (50 mg, 40%).

[0794] MS APCI+ve ^(m)/z 295/297 [(M+H)⁺].

[0795]¹H NMR 300 MHz (d₆-DMSO) 8.05 (1H, d), 7.87 (1H, s), 7.75 (1H, d),7.65 (1H, d), 6.65 (1H, s), 6.51 (2H, s), 5.77-5.89 (1H, m), 2.95 (2H,t), 2.10-2.44 (2H, m),

EXAMPLE 73

[0796]4-Chloro-5-fluoro-2-[[(1R)-1-(3-furanyl)-3-methylamino)propyl]oxy]-benzonitrile

[0797] a)[(3R)-3-(5-Chloro-2-cyano-4-fluorophenoxy)-3-(3-furanyl)propyl]carbamicacid 1,1-dimethylethyl ester

[0798] The product from Example 72(c) (460 mg, 1.17 mmol) was dissolvedin anhydrous tetrahydrofuran (10 ml) and sodium hydride (60%, 104 mg,2.6 mmol) added in one portion. The reaction was stirred for 10 minutes,then methyl iodide (0.66 ml, 10.53 mmol) was added and the reactionstirred for 24 h at room temperature. The reaction was quenched withaqueous saturated ammonium chloride solution (30 ml) and the mixtureextracted with ethyl acetate (3×70 ml). The combined extracts werewashed with water (3×30 ml), dried (sodium sulphate) and evaporated iiivacuo to give the title compound (360 mg, 75%).

[0799]¹H NMR 300 MHz (CDCl₃) 7.42 (2H, d), 7.26-7.36 (1H, m), 6.99 (1H,d), 6.42 (1H, s), 5.16 -5.26 (1H, m), 3.27-3.56 (2H, m), 2.87 (3H, s),2.21-2.43 (1H, m), 2.02-2.20 (1H, m), 1.40 (9H, s).

[0800] b)4-Chloro-5-fluoro-2-[[(1R)-1-(3-furanyl)-3-methylamino)propyl]oxy]-benzonitrilefumarate

[0801] Using the product from step (a) (355 mg, 0.87 mmol) and theprocedure described in Example 72(d), the title compound was prepared asa white solid (210 mg, 78%).

[0802] MS APCI+ve ^(m)/z 309/311 [(M+H)⁺].

[0803]¹H NMR 300 MHz (d₆-DMSO) 7.98 (1H, d), 7.80 (1H, s), 7.68 (1H, t),7.61 (1H, d), 6.53 (1H, t), 6.44 (2H, s), 5.76 (1H, t), 2.90 (2H, t),2.57 (3H, s), 2.33 (1H, quintet), 2.17 (1H, m).

EXAMPLE 74

[0804]4-Chloro-5-fluoro-2-[[(1R)-3-(methylamino)-1-(3-thienyl)propyl]oxy]benzonitrileoxalate

[0805] a) N-Methoxy-N-methyl-3-thiophene carboxamide

[0806] 3-Thiophene carboxylic acid (10.04 g, 78.3 mmol) was dissolved indichloromethane (250 ml) and 4-dimethylaminopyridine (9.57 g, 78.3mmol), N,O-dimethylhydroxylamine hydrochloride (7.64 g, 78.3 mmol),N-methylmorpholine (8.6 ml, 78.3 mmol) and1-(3-dimethylaminopropyl)-3-ethylcabodiimide hydrochloride (15.01 g,78.3 mmol) added and the resultant solution stirred for 24 h at roomtemperature. The reaction was diluted with dichloromethane (100 ml) andwashed with aqueous 2M hydrochloric acid (3×30 ml), aqueous saturatedsodium bicarbonate solution (2×30 ml) and water (3×30 ml). The organicphase was dried (magnesium sulphate), filtered and evaporated to givethe title compound as a colourless oil (12.3 g, 92%).

[0807]¹H NMR 300 MHz (CDCl₃) 8.07 (1H, dd), 7.58 (1H, dd), 7.26-7.33(1H, m), 3.66 (3H, s), 3.37 (3H, s).

[0808] b) 1-(3-Thienyl)-2-propen-1-one

[0809] The product from step (a) (2.074 g, 12.1 mmol) was dissolved inanhydrous tetrahydrofuran (30 ml) and the solution cooled to −10° C.Vinyl magnesium bromide (1M, 14.5 ml, 14.5 mmol) was added dropwise,keeping the temperature below 0° C. The resultant solution was stirredat 0° C. for 2.5 h, then allowed to warm to room temperature. Thereaction mixture was slowly poured into aqueous 2M hydrochloric acid(200 ml) and ice. Extracted with ethyl acetate (3×70 ml) and thecombined extracts were washed with water (2×30 ml) and brine (20 ml),dried (magnesium sulphate) and evaporated in vacuo to give the titlecompound (1.288 g, 77%).

[0810]¹H NMR 300 MHz (CDCl₃) 8.06-8.12 (1H, m), 7.58-7.64 (1H, m),7.32-7.39 (1H, m), 6.99-7.12 (1H, m), 6.46 (1H, dd), 5.89 (1H, dd).

[0811] c) 3-Chloro-1-(3-thienyl)-1-propanone

[0812] The product from step (b) (1.288 g, 9.3 mmol) was dissolved in amixture of diethyl ether (30 ml) and dichloromethane (20 ml) and 1Mhydrochloric acid in diethyl ether (25 ml) added. The reaction wasstirred for 18 h at room temperature. The solvent was removed in vacuoto give the title compound (1.482 g, 91%).

[0813]¹H NMR 300 MHz (CDCl₃) 8.02-8.12 (1H, m), 7.51-7.61 (1H, m),7.30-7.40 (1H, m), 3.90 (2H, t), 3.37 (2H, t).

[0814] d) (R)-α-(2-Chloroethyl)-3-thiophenemethanol

[0815] Using the procedure described in Example 72(b) and3-chloro-1-(3-thienyl-1-propanone (984 mg, 5.6 mmol), the title compoundwas prepared as a colourless oil (647 mg, 65%).

[0816]¹H NMR 300 MHz (CDCl₃) 7.29-7.36 (1H, m), 7.20-7.27 (1H, m),7.04-7.12 (1H, m), 5.02-5.09 (1H, m), 3.70-3.82 (1H, m), 3.52-3.62 (1H,m), 2.08-2.34 (2H, m), 1.95 (1H, d).

[0817] e)4-Chloro-2-[[(1R)-3-chloro-1-(3-thienyl)-propyl]oxy]-5-fluoro-benzonitrile

[0818] Using the product of step (d) (322 mg, 1.84 mmol),4-chloro-2,5-difluorobenzonitrile (320 mg, 1.84 mmol) and the proceduredescribed in Example 72(c), the title compound was prepared (540 mg,89%).

[0819]¹H NMR 300 MHz (CDCl₃) 7.35-7.40 (1H, m), 7.29-7.34 (1H, m),7.25-7.28 (1H, m), 7.11 (1H, dt), 6.95-6.99 (1H, m), 5.54-5.63 (1H, m),3.78-3.90 (1H, m), 3.55-3.66 (1H, m), 2.53-2.65 (1H, m), 2.21-2.35 (1H,m).

[0820] f)4-Chloro-5-fluoro-2-[[(1R)-3-iodo-1-(3-thienyl)-propyl]oxy]benzonitrile

[0821] Using the procedure described in Example 5(b) and4-chloro-2-[[(1R)-3-chloro-1-(3-thienyl)propyl]oxy]-5-fluorobenzonitrile(520 mg, 1.57 mmol), the title compound was prepared (640 mg, 97%).

[0822]¹H NMR 300 MHz (CDCl₃) 7.35-7.39 (1H, m), 7.29-7.34 (2H, m),7.09-7.12 (1H, m), 6.95-6.99 (1H, m), 5.42-5.51 (1H, m), 3.37-3.47 (1H,m), 3.16-3.26 (1H, m), 2.51-2.61 (1H, m), 2.26-2.38 (1H, m).

[0823] g)4-Chloro-5-fluoro-2-[[(1R)-3-(methylamino)-1-(3-thienyl)propyl]oxy]benzonitrileoxalate

[0824] Using the product of step (f) (210 mg, 0.5 mmol) and theprocedure described in Example 5(c), with oxalic acid replacinghydrochloric acid, the title compound was prepared (148mg,,71%).

[0825] MS APCI+ve ^(m)/z 325/327 [(M+H)⁺].

[0826]¹H NMR 300 MHz (d₆-DMSO) 8.01 (1H, d), 7.58-7.64 (2H, m), 7.51(1H, d), 7.12-7.16 (1H, m), 5.80-5.90 (1H, m), 2.90-3.08 (2H, m), 2.63(3H, s), 2.30-2.43 (1H, m), 2.13-2.28 (1H, m).

EXAMPLE 75

[0827]4-Chloro-5-fluoro-2-[[(1R)-3-[(2-hydroxyethyl)amino]-1-(3-thienyl)propyl]oxy]benzonitrileoxalate

[0828] The product from Example 74(f) (200 mg, 0.47 mmol) was dissolvedin anhydrous tetrahydrofuran (40 ml), ethanolamine (5 ml) added and themixture stirred for 3 days at room temperature. Water (30 ml) was addedand the reaction extracted with ethyl acetate (3×60 ml). The combinedorganic extracts were washed with water (3×20 ml), dried (magnesiumsulphate) and evaporated in vacuo. The residue was chromatographed onflash silica, eluting with 10% 7N ammonia in methanol indichloromethane, and the product dissolved in methanol and treated withone equivalent of oxalic acid. The mixture was stirred for 10 minutesthen the solvent removed in vacuo and the residue triturated in ethylacetate. The white solid was filtered and dried to afford the titlecompound. MS APCI+ve ^(m)/z 355/357 [(M+H)⁺].

[0829]¹H NMR 300 MHz (d₆-DMSO) 8.01 (1H, d), 7.61 (2H, t), 7.52 (1H, d),7.08-7.17 (1H, m), 5.79-5.93 (1H, m), 3.64 (2H, t), 3.03 (4H, dd),2.32-2.47 (1H, m), 2.18-2.32 (1H, m).

EXAMPLE 76

[0830]2-[[(1R)-3-[(2-aminoethyl)amino]-1-(3-thienyl)propyl]oxy]-4-chloro-5-fluoro-benzonitrileoxalate

[0831] The product from Example 74(f) (200 mg, 0.47 mmol) was dissolvedin anhydrous tetrahydrofuran (40 ml) ,ethylene diamine (5 ml) added andthe mixture stirred for 3 days at room temperature. Water (30 ml) wasadded and the reaction extracted with ethyl acetate (3×60 ml). Thecombined organic extracts were washed with water (3×20 ml), dried(magnesium sulphate) and evaporated in vacuo. The residue waschromatographed on flash silica, eluting, with 10% 7N ammonia inmethanol in dichloromethane, and the product dissolved in methanol andtreated with one equivalent of oxalic acid. The mixture was stirred for10 minutes then the solvent removed in vacuo and the residue trituratedin ethyl acetate. The white solid was filtered off and dried to affordthe title compound.

[0832] MS APCI+ve ^(m)/z 354/356 [(M+H)⁺].

[0833]¹H NMR 300 MHz (d₆-DMSO) 8.00 (1H, d), 7.56-7.68 (2H, m), 7.52(1H, d), 7.15 (1H, dd), 5.72-6.01 (1H, m), 3.01-3.14 (4H, m), 2.91-3.01(2H, m), 2.25-2.42 (1H, m), 2.12 -2.24 (1H, m).

EXAMPLE 77

[0834]2-[[(1R)-3-Amino-1-(3-thienyl)propyl]oxy]-4-chloro-5-fluorobenzonitrileoxalate

[0835] a)2-[[(1R)-3-Azido-1-(3-thienyl)propyl]oxy]-4-chloro-5-fluorobenzonitrile

[0836] The product of Example 74(e) (540 mg, 1.64 mmol) was dissolved inanhydrous dimethyl sulfoxide (20 ml) and sodium azide (170 mg, 2.62mmol) added. The reaction was heated s to 65° C. and stirred for 12 h,cooled and water (60 ml) added. The mixture was extracted with ethylacetate (3×70 ml) and the combined extracts washed with water (5×50 ml),dried (magnesium sulphate) and evaporated in vacuo to give the titlecompound (535 mg, 97%).

[0837]¹H NMR 300 MHz (CDCl₃) 7.35-7.41 (1H, m), 7.27-7.34 (2H, m),7.07-7.11 (1H, m), 6.91-6.95 (1H, m), 5.38-5.47 (1H, m), 3.58-3.70 (1H,m), 3.39-3.51 (1H, m), 2.28-2.45 (1H, m), 2.02-2.20 (1H, m).

[0838] b)2-[[(1R)-3-Amino-1-(3-thienyl)propyl]oxy]-4-chloro-5-fluorobenzonitrileoxalate

[0839] The product from step (a) (529 mg, 1.57 mmol) was dissolved inanhydrous tetrahydrofuran (80 ml), triphenylphosphine (1.235 g, 4.71mmol) added and the reaction mixture stirred for 1 h at roomtemperature. Water (5 ml) was added and the reaction stirred for 64 h.Water (100 ml) was added and the reaction extracted with ethyl acetate(4×70 ml). The combined organic extracts were washed with water (3×25ml), dried (sodium sulphate) and evaporated in vacuo. The residue waschromatographed on flash silica, eluting with 5% 7N ammonia in methanolin dichloromethane, and the product dissolved in methanol and treatedwith one equivalent of oxalic acid. The mixture was stirred for 10minutes then the solvent removed in vacuo and the solid residuetriturated with ethyl acetate. The white solid was filtered off anddried to give the title compound (380 mg, 60%).

[0840] MS APCI+ve ^(m)/z 311/313 [(M+H)⁺].

[0841]¹H NMR 300 MHz (d₆-DMSO) 8.01 (1H, d), 7.55-7.67 (2H, m), 7.47(1H, d), 7.13 (1H, dd), 5.85 (1H, dd), 2.81-2.99 (2H, m), 2.25-2.39 (1H,m).

EXAMPLE 78

[0842] 4-Chloro-2-[3-(methylamino)-1-(2-thiazolyl)propoxy]-benzonitrileoxalate

[0843] a) [3-Hydroxy-3-(2-thiazolyl)propyl]methylcarbamic acid1,1-dimethylethyl ester

[0844] 2-Bromothiazole (482 mg, 2.94 mmol) was dissolved in anhydroustetrahydrofuran (15 ml) and the solution cooled to −78° C.n-Butyllithium (2.4M, 1.25 ml, 3.0 mmol) was added dropwise and thereaction stirred for a half hour at −70° C. This solution was then addeddropwise to a solution of 1,1-dimethylethylestermethyl(3-oxopropyl)-carbamic acid (600 mg, 3.2 mmol) in anhydroustetrahydrofuran (15 ml) at −78° C. After the addition was complete, thereaction was allowed to warm slowly to room temperature overnight.Aqueous saturated ammonium chloride solution (20 ml) was added and thereaction extracted with ethyl acetate (3×70 ml). The combined extractswere washed with water (20 ml), dried (magnesium sulphate) andevaporated in vacuo. The residue was chromatographed on flash silica,eluting with ethyl acetate, to give the title compound as a pale orangeoil (320 mg, 40%).

[0845]¹H NMR 300 MHz (CDCl₃) 7.72 (1H, d), 7.28 (1H, d), 5.32-5.44 (1H,bs), 4.85-4.94 (1H, m), 3.88-4.01 (1H, m), 2.99-3.12 (1H, m), 2.90 (3H,s), 2.80-2.89 (1H, m), 2.26-2.41 (1H, m), 1.77-1.91 (1H, m), 1.50 (9H,s).

[0846] b)[3-(5-Chloro-2-cyanophenoxy)-3-(2-thiazolyl)propyl]methylcarbamic acid1,1-dimethylethyl ester

[0847] The product from step (a) (312 mg, 1.15 mmol),2-hydroxy-4-chlorobenzonitrile (176 mg, 1.15 mmol) andtriphenylphosphine (330 mg, 1.26 mmol) were dissolved in anhydroustetrahydrofuran (20 ml) and the solution cooled to 0° C. Diethylazodicarboxylate (219 mg, 1.26 mmol) was added dropwise and the solutionallowed to warm to room temperature slowly and stirred for 18 h. Thesolvent was removed in vacuo and the residue chromatographed on flashsilica, eluting with hexane:ethyl acetate (1:1) to give the titlecompound (200 mg, 43%).

[0848]¹H NMR 300 MHz (CDCl₃) 7.79 (1H, d), 7.34-7.53 (2H, m), 6.92-7.09(2H, m), 5.61 -5.71 (1H, m), 3.52-3.74 (1H, m), 3.31-3.45 (1H, m), 2.91(3H, s), 2.82-2.92 (1H, m), 2.24-2.48 (1H, m), 1.40 (9H, s).

[0849] c)4-Chloro-2-[3-(methylamino)-1-(2-thiazolyl)propoxy]benzonitrile oxalate

[0850] The product from step (b) (200 mg, 0.49 mmol) was dissolved in 4Mhydrochloric acid in dioxan and stirred for 2.5 h. The solvent wasremoved in vacuo and the residue applied to an acidic SCX resin, washedwith methanol (150 ml) and liberated the product with 7N ammonia inmethanol (50 ml). The solvent was evaporated in vacuo and the residuedissolved in methanol (5 ml) and treated with one equivalent of oxalicacid. Stirred for 15 minutes then removed the solvent in vacuo andtriturated the residue with a little ethyl acetate. The white solid wasfiltered off and dried to give the, title compound (17 mg, 11%).

[0851] MS APCI+ve ^(m)/z 308/310 [(M+H)⁺].

[0852]¹H NMR 300 MHz (d₆-DMSO) 7.79-7.93 (3H, m), 7.51 (1H, d), 7.26(1H, dd), 6.20-6.29 (1H, m), 3.07 (2H, t), 2.59 (3H, s), 2.39-2.62 (2H,m).

EXAMPLE 79

[0853]2-[[1R)-3-Amino-1-(2-thiazolyl)propyl]oxy]-4-chloro-5-fluoro-benzonitrilehydrochloride

[0854] a) [3-Oxo-3-[5-(trimethylsilyl)-2-thiazolyl]propyl]carbamic acid1,1-dimethylethyl ester

[0855] Using 2-(trimethylsilyl)thiazole (2.59 g, 16.5 mmol) and theprocedure described in Example 72(a), with the modification of stirringfor 2 h at −70° C. after the additions are complete and quenching at−65° C., the title compound was prepared (1.48 g, 55%).

[0856]¹H NMR 300 MHz (CDCl₃) 7.60 (1H, s), 4.76 (1H, s), 3.21 (2H, q),2.91-3.08 (2H, m) 1.12 (9H, s), 0.01 (9H, s).

[0857] b)[(3R)-3-hydroxy-3-[5-(trimethylsilyl)-2-thiazolyl]propyl]carbamic acid1,1-dimethylethyl ester

[0858] The product from step (a) (1.47 g, 4.47 mmol) and the proceduredescribed in Example 72(b) were used to prepare the title compound (700mg, 47%).

[0859]¹H NMR 300 MHz (CDCl₃) 7.42 (1H, s), 4.68-4.79 (1H, m), 4.64 (1H,s), 4.28 (1H, s), 3.18-3.37 (1H, m), 2.79-2.95 (1H, m), 1.77-1.92 (1H,m), 1.51-1.65 (1H, m), 1.14 (9H, s), 0.03 (9H, s).

[0860] c)[(3R)-3-(5-Chloro-2-cyano-4-fluorophenoxy)-3-(2-thiazolyl)propyl]carbamicacid, 1,1-dimethylethyl ester

[0861] The product from step (b) and the procedure described in Example72(c) were used to prepare the title compound (376 mg, 43%).

[0862]¹H NMR 300 MHz (CDCl₃) 7.79 (1H, d), 7.31-7.42 (2H, m), 7.14 (1H,d), 5.66 (1H, dd), 4.79 (1H, s), 3.44-3.60 (1H, m), 3.22-3.33 (1H, m),2.36-2.51 (1H, m), 2.20-2.34 (1H, m), 1.43 (9H, s).

[0863] d)2-[[(1R)-3-Amino-1-(2-thiazolyl)propyl]oxy]-4-chloro-5-fluoro-benzonitrilehydrochloride

[0864] The product from step (c) (370 mg, 0.9 mmol) was dissolved in 4Mhydrochloric acid in dioxan and stirred at room temperature for a halfhour. The solvent was removed in vacuo and the residue triturated with amixture of ethyl acetate and methanol (14:1). The white solid wasfiltered and dried to afford the title compound (243 mg, 70%).

[0865] MS APCI+ve ^(m)/z 312/314 [(M+H)⁺].

[0866]¹H NMR 300MHz (d₆-DMSO) 8.23 (3H, br s), 8.08 (1H, d), 7.9 (1H,d), 7.85(1H, d), 7.74 (1H, d), 6.29 (1H, dd), 2.90-3.07 (2H, m),2.35-2.48 (2H, m).

EXAMPLE 80

[0867] γ-(2-Chloro-5-nitrophenoxy)-N-methylbenzenepropanaminehydrochloride

[0868] a) [3-(2-Chloro-5-nitrophenoxy)-3-phenylpropyl]methylcarbamicacid 1,1-dimethylethyl ester

[0869] This was prepared by the method of Example 2 usingα-[2-(methylamino)ethyl]benzenemethanol and 2-chloro-5-nitrophenol.

[0870] MS APCI+ve ^(m)/z 321/323 [(M-Boc+H)⁺].

[0871] b) γ-(2-Chloro-5-nitrophenoxy)-N-methylbenzenepropanaminehydrochloride

[0872] [3-(2-Chloro-5-nitrophenoxy)-3-phenylpropyl]methylcarbamic acid,1,1-dimethylethyl ester (132 mg, 0.282 mmol) was stirred in 4N HCl indioxane (1 ml) for 16 h, and the resulting solid filtered off to givethe product as the hydrochloride salt (60 mg).

[0873] MS APCI+ve ^(m)/z 321/323 [(M+H)⁺].

[0874]¹H NMR 300 MHz (d₆-DMSO) 8.89−8.73 (2H, br m), 7.83−7.73 (3H, m),7.47−7.39 (4H, m), 7.36−7.30 (1H, m), 5.92 (1H, m), 3.11−3.00 (2H, m),2.58 (3H, s), 2.42−2.31 (1H, m), 2.28−2.18 (1H, m).

EXAMPLE 81

[0875] (R)-γ-(5-Chloro-2-nitrophenoxy)-N-methylbenzene)propanaminefumarate

[0876] a)[(3R)-3-(5-Chloro-2-nitrophenoxy)-3-phenylpropyl]methylcarbamic acid,1,1-dimethylethyl ester

[0877] This was prepared by the method of Example 20(a) using[(3S)-3-hydroxy-3-phenylpropyl]methylcarbamic acid 1,1-dimethylethylester and 5-chloro-2-nitrophenol.

[0878] APCI+ve ^(m)/z 32 1/323 [(M-BOC+H)⁺].

[0879] b) (R)-γ-(5-Chloro-2-nitrophenoxy)-N-methylbenzene)propanaminefumarate

[0880] This was prepared by the method of Example 20(b), the productbeing isolated as the fumarate salt.

[0881] MS APCI+ve ^(m)/z 321/323 [(M+H)⁺].

[0882]¹H NMR 400 MHz (d₆-DMSO) 7.92 (1H, d), 7.45−7.39 (4H, m),7.36−7.31 (1H, m), 7.27 (1H, d), 7.14 (1H, m), 6.46 (2H, s), 5.88 (1H,m), 2.96−2.86 (2H, m), 2.50 (3H, s), 2.29−2.19 (1H, m), 2.17−2.09 (1H,m).

EXAMPLE 82

[0883]4-Chloro-5-fluoro-2-{[(1R)-3-[(2-fluoroethyl)amino]-1-phenylpropyl]oxy}benzonitrileoxalate

[0884] This was prepared by the method of Example 43(b) using2-fluoroethylamine and4-chloro-2-{[(1R)-3-chloro-1-phenylpropyl]oxy}-5-fluorobenzonitrile. Thefree base was converted into the oxalate salt.

[0885] MS APCI+ve ^(m)/z 351 [(M+H)⁺].

[0886]¹H NMR 400 MHz (d₆-DMSO) 8.02 (1H, d), 7.46−7.41 (5H, m),7.38−7.33 (1H, m), 5.80−5.76 (1H, m), 4.73 (1H, t), 4.61 (1H, t),3.4−3.2 (2H, m), 3.15−3.0 (2H, m), 2.4−2.3 (1H, m), 2.21−2.10 (1H, m).

EXAMPLE 83

[0887] 2-[[(1R)-3-Amino-1-phenylpropyl]oxy]-4-bromo-5-fluorobenzonitrileoxalate

[0888] a) 4-Bromo-2,5-difluorobenzaldehyde

[0889] n-Butyllithium (1.95M in hexanes, 10.2 ml)) was added dropwise toa stirred solution of 1,4-dibromo-2,5-difluorobenzene (5 g, 18.4 mmol)in diethyl ether (60 ml) at −70° C. After 1 h, the solution was warmedto 0° C. over 1 h, diluted with water, the layers separated and theether layer dried over sodium sulphate and evaporated. Purification bycolumn chromatography (Biotage), eluting with 5% ethyl acetate/hexane,gave a yellow oil (1.82 g).

[0890]¹H NMR 300 MHz (CDCl₃) 10.28 (1H, s), 7.61 (1H, dd), 7.48 (1H,dd).

[0891] b) 4-Bromo-2,5-difluorobenzonitrile

[0892] 4-Bromo-2,5-difluorobenzaldehyde (1.82 g, 8.3 mmol) andhydroxylamin-O-sulphonic acid (1.1 eq., 1.03 g) in water (40 ml) wereheated to 100° C. for 6 h, cooled and extracted with ethyl acetate. Theorganic layer was dried (sodium sulphate) and evaporated to give thetitle compound as a pale yellow solid (1.2 g).

[0893]¹H NMR 300 MHz (CDCl₃) 7.51 (1H, t), 7.39 (1H, t).

[0894] (c)4-Bromo-2-[[(1R)-3-chloro-1-phenylpropyl]oxy]-5-fluorobenzonitrile

[0895] This was prepared by the method of Example 43(a) using4-bromo-2,5-difluorobenzonitrile and(R)-α-(2-chloroethyl)benzenemethanol.

[0896]¹H NMR 300 MHz (CDCl₃) 8.02 (1H, s), 7.42−7.26 (5H, m), 7.06−7.03(1H, m), 5.46−5.43 (1H, m), 3.82−3.62 (1H, m), 3.75−3.60 (1H, m),2.75−2.5 (1H, m), 2.55−2.30 (1H, m).

[0897] d)2-[[(1R)-3-Azido-1-phenylpropyl]oxy]-4-bromo-5-fluorobenzonitrile

[0898] This was prepared by the method of Example 68(b) using4-bromo-2-[[(1R)-3-chloro-1-phenylpropyl]oxy]-5-fluorobenzonitrile andsodium azide.

[0899] MS APCI+ve ^(m)/z 351 [(M−N₂+H)⁺].

[0900] e)2-[[(1R)-3-Amino-1-phenylpropyl]oxy]-4-bromo-5-fluorobenzonitrileoxalate

[0901] This was prepared by the method of Example 77(b) using2-[[(1R)-3-azido-1-phenylpropyl]oxy]-4-bromo-5-fluorobenzonitrile.

[0902] MS APCI+ve ^(m)/z 349/350 [(M+H)⁺].

[0903]¹H NMR 400 MHz (d₆-DMSO) 7.96 (1H, d), 7.48−7.40 (5H, m),7.36−7.32(1H, m), 5.79−5,75 (1H, dd), 2.95-2.82 (2H, m), 2.32−2.20 (1H, m), 2.10(1H, m).

EXAMPLE 84

[0904] 3-[[(3R)-3-(2,5-dichlorophenoxy)-3-phenylpropyl]amino]-1-propanolhydrochloride

[0905] a) 1.4-Dichloro-2-[[(1R)-3-chloro-1-phenylpropyl]oxy]benzene,

[0906] 2,5-Dichlorophenol (1.65 g) was subjected to the proceduredescribed for Example 5(a) to afford the product as a clear oil (2.26g).

[0907]¹H NMR 300 MHz (CDCl₃) 7.39−7.36 (5H, m), 7.24 (1H, s), 6.82 (1H,dd), 6.74 (1H, d), 5.40 (1H, dd), 3.93−3.80 (1H, m), 3.69−3.57 (1H, m),(2.33−2.18 (1H, m).

[0908] b) 1,4-Dichloro-2-[[(1R)-3-iodo-1-phenylpropyl]oxy]benzene,

[0909] The product from step (a) (2.26 g) was subjected to the proceduredescribed for Example 5 (b) to afford the product as a yellow oil (2.78g).

[0910]¹H NMR 300 MHz (CDCl₃) 7.39−7.36 (5H, m), 7.25−7.23 (1H, m),6.84−6.80 (1H, m). 6.76−6.73 (1H, m), 5.32−5.25 (1H, m), 3.50−3.39 (1H,m), 3.33−3.24 (1H, m), 2.60−2.49 (1H, m), 2.39−2.26 (1H, m).

[0911] c)3-[[(3R)-3-(2,5-Dichlorophenoxy)-3-phenylpropyl]amino]-1-propanolhydrochloride

[0912] The product of step (b) (0.2 g) and 3-amino-propanol (0.11 g)were dissolved in dimethylformamide (4 ml) and stirred for 24 h. Thereaction was poured into water and extracted into ethyl acetate. Theorganic extract was washed with brine, dried over magnesium sulphate andevaporated to dryness and triturated with 1N HCl in ether to give theproduct as a white solid.

[0913] MS APCI+ve ^(m)/z 354 [(M+H)⁺].

[0914]¹NMR (d₆-DMSO) 8.76 (1H, s), 7.50−7.37 (6H, m), 7.09 (1H, d), 6.99(1H, dd), 5.77 (1H, dd), 4.73 (1H, s), 3.47 (2H, t), 3.11−2.91 (4H, m),2.39−2.26 (1H, m), 2.26−2.14 (1H, m), 1.80−1.67 (2H, m).

EXAMPLE 85

[0915]1-[(3R)-3-(2,5-Dichlorophenoxy)-3-phenylpropyl]-4-piperidinemethanolhydrochloride

[0916] The product of Example 84(b) (0.2 g) and 4-piperidinemethanol(0.11 g) were subjected to the procedure described in Example 84(c) togive the product as a white solid.

[0917] MS APCI+ve ^(m)/z 394 [(M+H)⁺].

[0918]¹H NMR 300 MHz (d₆-DMSO) 9.97 (1H, s), 7.48−7.28 (6H, m), 7.11(1H, d), 6.99 (1H, dd), 5.77−5.67 (1H, m), 4.68−4.58 (1H, m), 3.56−3.44(2H, m)m 3.28−3.20 (2H, m), 3.19−3.07 (2H, m), 2.99−2.83 (2H, m),1.86−1.74 (2H, m), 1.68−1.53 (1H, m), 1.51−1.35 (2H, m), 2.44−2.24 (2H,m).

EXAMPLE 86

[0919]N-[(3R)-3-(2,5-Dichlorophenoxy)-3-phenylpropyl]-2-thiophenemethanaminehydrochloride

[0920] The product of Example 84(b) (0.2 g) and 2-thiophenemethanamine(0.06 ) were subjected to the procedure described in Example 84(c) togive the product as a white solid.

[0921] MS APCI+ve ^(m)/z 392 [(M+H)⁺].

[0922]¹H NMR 400 MHz (d₆-DMSO) 9.40−9.24 (2H, m), 7.63 (1H, dd),7.49−7.36 (5H, m), 7.36−7.28 (2H, m), 7.12−7.05 (2H, m), 7.03−6.95 (1H,m), 5.83−5.74 (1H, m), 4.46−4.37 (2H, m), 3.16−2.97 (2H, m), 2.40−2.29(1H, m), 2.28−2.18 (1H, m).

EXAMPLE 87

[0923]N-[(3R)-3-(2,5-dichlorophenoxy)-3-phenylpropyl]-5-methyl-2-furanmethanaminehydrochloride

[0924] The product of Example 84(b) (0.2 g) and5-methyl-2-furanmethanamine (0.06 g) were subjected to the proceduredescribed in Example 84(c) to give the product as a white solid.

[0925] MS APCI+ve ^(m)/z 390 [(M+H)⁺].

[0926]¹H NMR 300 MHz (d₆-DMSO) 9.36−9.17 (2H, m), 7.51−7.29 (6H, m),7.10−7.04 (1H, m), 7.02−6.94 (1H, m), 6.48 (1H, d), 6.12 (1H, dd),5.82−5.71 (1H, m), 4.20 (2H, s), 3.12−2.94 (2H, m), 2.39−2.13 (2H, m),2.26 (3H, s).

EXAMPLE 88

[0927]4-Chloro-2-[[(1R)-1-phenyl-3-(1-piperazinyl)propyl]oxy]benzonitriledihydrochloride

[0928] a) 1,1-Dimethylethyl4-[(3R)-3-(5-chloro-2-cyanophenoxy)-3-phenylpropyl]-1-piperazinecarboxylate

[0929] 4-Chloro-2-{[(1R)-3-chloro-1-phenylpropyl]oxy}benzonitrile (0.3g) and 1,1-dimethylethyl piperazinecarboxylate (0.4 g) were subjected tothe procedure described for Example 11 to give the product as a cleargum (0.35 g).

[0930]¹H NMR 400 MHz (CDCl₃) 7.45 (1H, d), 7.41−7.34 (5H, m), 6.92 (1H,dd), 6.86 (1H, d), 5.36 (1H, dd), 3.49−3.34 (4H, m), 2.62−2.21 (7H, m),2.11−1.96 (1H, m), 1.47 (9H, d).

[0931] b)4-Chloro-2-[[(1R)-1-phenyl-3-(1-piperazinyl)propyl]oxy]-benzonitriledihydrochloride

[0932] The product from step (a) (0.35 g) was stirred in 4M HCl indioxane (10 ml) for 3 h, then poured into saturated sodium bicarbonatesolution (100 ml) and extracted into ethyl acetate. The extract wasevaporated to dryness and the residue triturated with 1N HCl in ether togive the product as a white solid.

[0933] MS APCI+ve ^(m)/z 356 [(M+H)⁺].

[0934]¹H NMR 400 MHz (d₆-DMSO) 9.81−9.42 (2H, m), 7.78 (1H, d),7.53−7.25 (6H, m), 7.15 (1H, d), 5.99−5.84 (1H, m), 3.94−3.03 (12H, m).

EXAMPLE 89

[0935]5-Fluoro-2-[[(1R)-3-[(2-Hydroxyethyl)amino]-1-(3-isoxazolyl)propyl]oxy]-4-methyl-benzonitrilefumarate

[0936] a) N-Methoxy-N-methyl-3-isoxazolecarboxamide,

[0937] A mixture of 3-isoxazolecarboxylic acid (4.2 g),4-dimethylaminopyridine (5.1 g), N,O-dimethylhydroxylamine hydrochloride(4.0 g), N-methylmorpholine (4.2 g) and1-(3-diethylaminopropyl)-3-ethylcarbodiimide hydrochloride (7.5 g) indichloromethane (175 ml) were stirred at ambient temperature overnight.The reaction mixture was then washed with 2N hydrochloric acid (100 ml),saturated sodium bicarbonate (100 ml), brine, dried over magnesiumsulphate and evaporated to give the product as a dark orange oil 5 (3.7g).

[0938]¹H NMR 300 MHz (CDCl₃) 8.48 (1H, d), 6.72 (1H, br s), 3.8 (3H, s),3.4 (3H, s).

[0939] b) 1-(3-Isoxazolyl)-2-propen-1-one

[0940] The product of step (a) (0.66 g) was dissolved in drytetrahydrofuran (20 ml), under a nitrogen atmosphere and cooled to −30°C. A solution of vinyl magnesium bromide (1M, 6 ml) was added dropwiseover 5 minutes and the reaction mixture was allowed to warm to 0° C. andstirred at this temperature for 2 h. The mixture was then poured intoice-cold 2N hydrochloric acid (50 ml) and extracted into ethyl acetate.The extract was washed with water, brine, dried over magnesium sulphateand evaporated to give a dark oil (0.4 g).

[0941]¹H NMR 300 MHz (CDCl₃) 8.53−8.48 (1H, m), 7.36−7.22 (1H, m),6.88−6.81 (1H, m), 6.76−6.64 (1H, m), 6.07−6.00 (1H, m).

[0942] c) 3-Chloro-1-(3-isoxazolyl)-1-propanone

[0943] The product of step (b) was treated with 1M HCl in ether (5 ml)and stirred for 4 h at ambient temperature. The solvent was then removedunder reduced pressure to leave the product as a dark gum (0.42 g).

[0944]¹H NMR 300 MHz (CDCl₃) 8.51 (1H, d), 6.79 (1H, d), 3.92 (2H, t),3.57 (2H, t).

[0945] d) (S)-α-(2-Chloroethyl)-3-isoxazolemethanol

[0946] The product of step (c) (1 g) was reduced by the proceduredescribed in Example 68(a) to give the product as a clear oil (0.5 g).

[0947]¹H NMR 300 MHz (CDCl₃) 8.47−8.36 (1H, m), 6.43−6.38 (1H, m), 5.18(1H, dt), 3.87−3.75 (1H, m), 3.73−3.62 (1H, m), 2.71−2.61 (1H, m),2.36−2.18 (2H, m).

[0948] e)2-[[(1R)-3-Chloro-1-(3-isoxazolyl)propyl]oxy]-5-fluoro-4-methyl-benzonitrile

[0949] The product of step (d) (0.47 g) was reacted with5-fluoro-2-hydroxy-4-methylbenzonitrile using the procedure describedfor Example 5(a) to afford the product as a white solid (0.4 g).

[0950]¹H NMR 300 MHz (CDCl₃) 8.42 (1H, t), 7.18 (1H, d), 6.94 (1H, d),6.47 (1H, d), 5.78 (1H, dd), 3.97−3.82 (1H, m), 3.80−3.67 (1H, m),2.73−2.56 (1H, m), 2.43−2.29 (1H, m), 2.31 (3H, s).

[0951] f)5-Fluoro-2-[[(1R)-3-[(2-hydroxyethyl)amino]-1-(3-isoxazolyl)propyl]oxy]-4-methyl-benzonitrilefumarate

[0952] The product of step (e) (0.16 g) was reacted with ethanolamine(0.3 g) using the procedure described for Example 11 to afford theproduct as a white solid (0.14 g).

[0953] MS APCI+ve ^(m)/z 320 [(M+H)⁺].

[0954]¹H NMR 300 MHz (d₆-DMSO) 8.97 (1H, s), 7.67 (1H, d), 7.26 (1H, d),6.68 (1H, s), 6.48 (2H, s), 5.93 (1H, s), 3.60 (2H, s), 2.96 (4H, d),2.47−2.35 (1H, m), 2.33−2.10 (4H, m).

EXAMPLE 90

[0955]2-[[(1R)-3-Amino-1-(3-isoxazolyl)propyl]oxy]-5-fluoro-4-methyl-benzonitrilefumarate

[0956] a) 2-[[(1R)-3-Azido -1-(3-isoxazolyl)propyl]oxy]-5-fluoro-4-methyl-benzonitrile

[0957] The product of Example 89(e) (0.2 g) and sodium azide (0.045 g)in dimethylsulphoxide (5 ml) were heated at 60° C. for 24 h to give theproduct.

[0958] MS APCI+ve ^(m)/z 274 [(M−28)⁺].

[0959] b)2-[[(1R)-3-Amino-1-(3-isoxazolyl)propyl]oxy]-5-fluoro-4-methyl-benzonitrilefumarate

[0960] The solution produced in step (a) was treated withtetrahydrofuran (10 ml), water (1 ml) and triphenylphosphine (0.3 g) andstirred at ambient temperature for 36 h. The mixture was poured intosaturated sodium bicarbonate (20 ml) and extracted into ethyl acetate.The extract was evaporated to dryness and the residue loaded onto an ionexchange resin (SCX isolute) and washed with acetonitrile and methanol.The product was eluted off the column with 7M ammonia in methanol togive an oil which was converted into the fumarate salt (0.104,g).

[0961] MS APCI+ve ^(m)/z 276 [(M+H)⁺].

[0962]¹H NMR 300 MHz (d₆-DMSO) 8.97 (1H, d), 7.68 (1H, d), 7.24 (1H, d),6.68 (1H, d), 6.41 (2H, s), 5.99−5.85 (1H, m), 3.01−2.89 (2H, m),2.43−2.29 (1H, m), 2.27−2.16 (1H, m), 2.24 (3H, s).

EXAMPLE 91

[0963]4-Chloro-2-[[(1R)-3-[(1,1-dimethylethyl)amino]-1-(3-isoxazolyl)propyl]oxy]benzonitrilefumarate

[0964] a) (R)-α-(2-Chloroethyl)-3-isoxazolemethanol

[0965] The product from Example 89(c) (3 g) was reduced using theprocedure described in Example 66(c) to give the product as clear oil(1,1 g).

[0966]¹H NMR 300 MHz (CDCl₃) 8.40 (1H, d), 6.40 (1H, d), 5.25−5.13 (1H,m), 3.88−3.61 (2H, m), 2.42 (1H, d), 2.33−2.21 (2H, m).

[0967] b)4-Chloro-2-[[(1R)-3-chloro-1-(3-isoxazolyl)propyl]oxy]benzonitrile

[0968] The product of step (a) (0.19 g) and2-fluoro-4-chlorobenzonitrile (0.17 g) were dissolved indimethylformamide (5 ml) and treated with sodium hydride (60% dispersionin oil, 0.06 g). After 2 h, the reaction was poured into 2N hydrochloricacid (10 ml) and extracted into ethyl acetate (50 ml). The extract waswashed with saturated sodium bicarbonate, brine, dried over magnesiumsulphate and evaporated down to a yellow oil (0.29 g).

[0969] MS APCI+ve ^(m)/z 298 [(M+H)⁺].

[0970]¹H NMR 300 MHz (CDCl₃) 8.44 (1H, d), 7.49 (1H, d), 7.13 (1H, d),7.04 (1H, dd), 6.46 (1H, d), 5.82 (1H, dd), 3.88 (1H, ddd), 3.73 (1H,dt), 2.73−2.57 (1H, m), 2.47−2.26 (1H, m).

[0971] c)4-Chloro-2-[[(1R)-3-[1,1-dimethylethyl)amino]-1-(3-isoxazolyl)propyl]oxy]benzonitrilefumarate

[0972] The product from step (b) (0.14 g) and tert-butylamine (0.5 g)were reacted using the procedure described for Example 12 to afford theproduct as a white solid (0.085 g).

[0973] MS APCI+ve ^(m)/z 334 [(M+H)⁺].

[0974]¹H NMR 300 MHz (d₆-DMSO) 8.96 (1H, d), 7.77 (1H, d), 7.40 (1H, d),7.20 (1H, dd), 6.71 (1H, t), 6.46 (2H, s), 6.15−5.90 (1H, m), 2.95 (2H,t), 2.45_31 2.34 (1H, m), 2.33−2.19 (1H, m), 1.22 (9H, s).

EXAMPLE 92

[0975]2-[[(1R)-3-Amino-1-(3-isoxazolyl)propyl]oxy]-4-chloro-benzonitrilefumarate

[0976] a)2-[[(1R)-3-Azido-1-(3-isoxazolyl)propyl]oxy]-4-chloro-benzonitrile

[0977] The product of Example 91(b) was subjected to the procedure inExample 90(a) to afford the product which was then carried on directlyto the next step.

[0978] b)2-[[(1R)-3-Amino-1-(3-isoxazolyl)propyl]oxy]-4-chloro-benzonitrilefumarate The product of step (a) (0.14 g) was subjected to the proceduredescribed in Example 90(b) to afford the product as a white solid (0.05g).

[0979] MS APCI+ve ^(m)/z 278 [(M+H)⁺].

[0980]¹H NMR 300 MHz (d₆-DMSO) 8.99 (1H, d), 7.81 (1H, d), 7.41 (1H, d),7.23 (1H, dd), 6.72 (1H, d), 6.41 (2H, s), 6.08 (1H, dd), 2.95 (2H, t),2.44−2.31 (1H, m), 2.31−2.19 (1H, m).

EXAMPLE 93

[0981]2-[[(1R)-3-Amino-1-(3-isoxazolyl)propyl]oxy]-4-chloro-5-fluoro-benzonitrile

[0982] a) (R)-α-(2-Azidoethyl)-3-isoxazolemethanol,

[0983] The product from Example 91(a) (0.17 g) and sodium azide (0.08 g)were heated in dimethylsulphoxide (3 ml) at 70° C. for 4 h. The mixturewas then poured into water and extracted with ethyl acetate. The extractwas washed with water, brine, dried over magnesium sulphate andevaporated to give the product as a clear oil (0.15 g).

[0984] MS APCI+ve ^(m)/z 141 [(M−28)⁺].

[0985]¹H NMR 300 MHz (CDCl₃) 8.47 (1H, d), 6.50 (1H, d), 5.18−4.98 (1H,m), 3.72−3.40 (2H, m), 2.70−2.47 (1H, m), 2.16−1.98 (2H, m).

[0986] b)2-[[(1R)-3-Azido-1-(3-isoxazolyl)propyl]oxy]-4-chloro-5-fluorobenzonitrile

[0987] The product from step (a) (0.1 g) and2,5-difluoro-4-chloro-benzonitrile (0.18 g) and sodium hydride (60%dispersion in oil, 0.035 g) were subjected to the procedure described inExample 90(a) to afford the product as a gum (0.15 g).

[0988] MS APCI+ve ^(m)/z 294 [(M−28)⁺].

[0989] c)2-[[(1R)-3-Amino-1-(3-isoxazolyl)propyl]oxy]-4-chloro-5-fluoro-benzonitrilefumarate

[0990] The product from step (b) (0.15 g) and triphenylphosphine (0.3 g)were subjected to the procedure described in Example 90(b) to afford theproduct as a solid (0.105 g).

[0991] MS APCI+ve ^(m)/z 296 [(M+H)⁺].

[0992]¹H NMR 300 MHz (d₆-DMSO) 8.99 (1H, d), 8.04 (1H, d), 7.61 (1H, d),6.74−6.68 (1H, m), 6.40 (2H, s), 6.09−6.00 (1H, m), 3.00−2.89 (2H, m),2.43−2.32 (1H, m), 2.29−2.18 (1H, m).

EXAMPLE 94

[0993] (R)-γ-(2,5-Dichlorophenoxy)-3-isoxazolepropanamine fumarate

[0994] a) 3-[(1R)-3-Azido-1-(2,5-dichlorophenoxy)propyl]isoxazole

[0995] The product from Example 93(a) (0.17 g) was reacted with2,5-dichloro-fluorobenzene (0.4 g) using the procedure described inExample 93(b) to afford the product as a gum which was carried on to thenext step.

[0996] b) (R)-γ-(2,5-Dichlorophenoxy)-3-isoxazolepropanamine fumarate

[0997] The product from step (a) (0.1 g) was subjected to the proceduredescribed in Example 90(b) to afford the product as a solid (0.03 g).

[0998] MS APCI+ve ^(m)/z 287 [(M+H)⁺].

[0999]¹H NMR 300 MHz (CD₃OD) 8.72 (1H, d), 7.39 (1H, d), 7.13 (1H, d),7.02 (1H, dd), 6.70 (2H, s), 6.56 (1H, d), 5.86−5.77 (1H, m), 3.28−3.19(2H, m), 2.60−2.46 (1H, m), 2.43−2.28 (1H, m).

[1000] Screens

[1001] The pharmacological activity of compounds according to theinvention was tested in the following screens.

[1002] Screen 1

[1003] The activity of compounds of formula (I), or a pharmaceuticallyacceptable salt, enantiomer or racemate thereof, may be screened fornitric oxide synthase inhibiting activity by a procedure based on thatof Förstermann et al., Eur. J. Pharm., 1992, 225, 161-165. Nitric oxidesynthase converts ³H-L-arginine into ³H-L-citrulline which can beseparated by cation exchange chromatography and quantified by liquidscintillation counting.

[1004] Enzyme is prepared, after induction, from the cultured murinemacrophage cell line J774A-1 (obtained from the laboratories of theImperial Cancer Research Fund). J774A-1 cells are cultured in DulbeccosModified Eagles Medium (DMEM) supplemented with 10% foetal bovine serum,4 MM L-glutamine and antibiotics (100 units/ml penicillin G, 100 mg/mlstreptomycin & 0.25 mg/ml amphotericin B). Cells are routinely grown in225 cm³ flasks containing 35 ml medium kept at 37° C. and in ahumidified atmosphere containing 5% CO₂.

[1005] Nitric oxide synthase is produced by cells in response tointerferon-g (IFNg) and lipopolysaccharide (LPS). The medium fromconfluent culture flasks is removed and replaced with 25 ml (per flask)of fresh medium containing 1 mg/ml LPS and 10 units/ml IFNg. After aperiod of 17-20 hours in culture, harvesting of cells is accomplished byscraping the cell sheet from the flask surface into the culture medium.Cells are collected by centrifugation (1000 g for 10 minutes) and lysateprepared by adding to the cell pellet a solution containing 50 mMTris-HCl (pH 7.5 at 20° C.), 10% (v/v) glycerol, 0.1% (v/v)Triton-X-100, 0.1 mM dithiothreitol and a cocktail of proteaseinhibitors comprising leupeptin (2 mg/ml), soya bean trypsin inhibitor(10 mg/ml), aprotinin (5 mg/ml) and phenylmethylsulphonyl fluoride (50mg/ml).

[1006] For the assay, 25 μl of substrate cocktail (50 mM Tris-HCl (pH7.5 at 20° C.), 400 μM NADPH, 20 μM flavin adenine dinucleotide, 20 μMflavin mononucleotide, 4 μM tetrahydrobiopterin, 12 μM L-arginine and0.025 mCi L-[³H] arginine) is added to wells of a 96 well filter plate(0.45 μM pore size) containing 25 μl of a solution of test compound in50 mM Tris-HCl. The reaction is started by adding 50 μl of cell lysate(prepared as above) and after incubation for 1 hour at room temperatureis terminated by addition of 50 μl of an aqueous solution of 3 mMnitroarginine and 21 mM EDTA.

[1007] Labelled L-citrulline is separated from labelled L-arginine usingDowex AG-50W. 150 μl of a 25% aqueous slurry of Dowex SOW (Na⁺ form) isadded to the assay after which the whole is filtered into 96 wellplates. 75 μl of filtrate is sampled and added to wells of 96 wellplates containing solid scintillant. After allowing the samples to drythe L-citrulline is quantified by scintillation counting.

[1008] In a typical experiment basal activity is 300 dpm per 75 μlsample which is increased to 1900 dpm in the reagent controls. Compoundactivity is expressed as IC₅₀ (the concentration of drug substance whichgives 50% enzyme inhibition in the assay) and aminoguanidine, whichgives an IC₅₀ (50% inhibitory concentration) of 10 μM, is tested as astandard to verify the procedure. Compounds are tested at a range ofconcentrations and from the inhibitions obtained IC₅₀ values arecalculated. Compounds that inhibit the enzyme by at least 25% at 100 μMare classed as being active and are subjected to at least one retest.

[1009] Screen 2

[1010] Compounds also show activity against the human form of inducednitric oxide synthase as can be demonstrated in the following assay.

[1011] The human colorectal carcinoma cell line, DLD-1 (obtained fromthe European Collection of Animal Cell Culture—cell line number90102540) was routinely grown in RPMI 1640 supplemented with 10%(v/v)foetal bovine serum, and 2 mM L-glutamine, at 37° C. in 5% CO₂

[1012] Nitric oxide synthase was induced in cells by addition of mediumcontaining human recombinant gamma-IFN (1000 units/ml), TNF-alpha (200U/ml), IL-6 (200 U/ml) and IL-1-beta (250 U/ml). After incubation for 18hours at 37° C., the medium was removed and the cells washed with warmphosphate buffered saline. Cells were incubated for a further 5 hours at37° C./5% CO₂ in RPMI 1640 containing 100 μM L-arginine and 100 μMverapamil-HCl in the presence and absence of test compounds.

[1013] Nitrite accumulation was determined by mixing an equal volume ofculture media with Griess reagent (10 mg/ml sulphanilamide, 1mg-N-(1-naphthyl)ethylenediamine in 1 ml 2.5% (v/v) phosphoric acid).Inhibition in the presence of compounds was calculated relative to thenitrite levels produced by untreated cells. IC₅₀ values were estimatedfrom a semi-log plot of % inhibition versus concentration of compound.

[1014] When tested, the compounds of Examples 1 to 94 gave IC₅₀ valuesof less than 25 μM in at least one of the above screens, indicating thatthey are predicted to show useful therapeutic activity.

1. The use of a compound of formula (I)

wherein: X and Y independently represent C1 to 4 alkyl, C1 to 4 alkoxy,halogen, CF₃, OCF₃, CN, C≡CH, S(O)_(m)CH₃, S(O)_(p)CF₃, NO₂ or NHCHO; mand p independently represent an integer 0, 1 or 2; Z represents H orfluoro; V represents O; W represents phenyl or a five or six memberedaromatic heterocyclic ring containing 1 to 3 heteroatoms independentlyselected from O, S and N; said phenyl or aromatic heterocyclic ringbeing optionally substituted by one or more substituents selectedindependently from halogen, C1 to 4 alkyl, C1 to 4 alkoxy, OH, CN, NO₂or NR⁴R⁵; said alkyl or alkoxy group being optionally farthersubstituted by one or more fluorine atoms; R¹ and R² independentlyrepresent H, C1 to 4 alkyl or C3 to 6 cycloalkyl; said alkyl group beingoptionally substituted by C1 to 4 alkoxy, halogen, hydroxy, NR⁶R⁷,phenyl or a five or six membered aromatic or saturated heterocyclic ringcontaining 1 to 3 heteroatoms independently selected from O, S and N;said phenyl or aromatic heterocyclic ring being optionally furthersubstituted by halogen, C1 to 4 alkyl, C1 to 4 alkoxy, CF₃, OCF₃, CN orNO₂; or the group NR¹R² together represents a 4 to 8 membered saturatedazacyclic ring optionally incorporating one further heteroatom selectedfrom O, S or NR⁸; said ring being optionally substituted by C1 to 4alkyl, C1 to 4 alkoxy or OH; said alkyl group being optionallysubstituted by C1 to 4 alkoxy, OH or NR⁹R¹⁰; or the group NR¹R² togetherrepresents part of a five membered aromatic azacyclic ring optionallyincorporating one further N atom; R⁴, R⁵R⁶, R⁷, R⁹ and R¹⁰ independentlyrepresent H or C1 to 4 alkyl; R⁸ represents H or C1 to 6 alkyl; saidalkyl group being optionally substituted by C1 to 4 alkoxy, OH, NR¹¹R¹²,phenyl or a five or six membered aromatic or saturated heterocyclic ringcontaining 1 to 3 heteroatoms independently selected from O, S and N;said phenyl or aromatic heterocyclic ring being optionally furthersubstituted by halogen, C1 to 4 alkyl, C1 to 4 alkoxy, CF₃, OCF₃, CN orNO₂; R¹¹ and R¹² independently represent H or C1 to 4 alkyl; or apharmaceutically acceptable salt, enantiomer or racemate thereof, in themanufacture of a medicament, for the treatment or prophylaxis ofdiseases or conditions in which inhibition of nitric oxide synthaseactivity is beneficial.
 2. The use as claimed in claim 1 wherein it ispredominantly inducible nitric oxide synthase that is inhibited.
 3. Theuse of a compound of formula (I) as defined in claim 1, or apharmaceutically acceptable salt, enantiomer or racemate thereof, in themanufacture of a medicament, for the treatment or prophylaxis ofinflammatory diseases.
 4. The use as claimed in claim 3 wherein thedisease is inflammatory bowel disease.
 5. The use as claimed in claim 3wherein the disease is rheumatoid arthritis.
 6. The use as claimed inclaim 3 wherein the disease is osteoarthritis.
 7. The use of a compoundof formula (I) as defined in claim 1, or a pharmaceutically acceptablesalt, enantiomer or racemate thereof, in the manufacture of amedicament, for the treatment or prophylaxis of pain.
 8. The use of acompound of formula (I) as defined in claim 1, or a pharmaceuticallyacceptable salt, enantiomer or racemate thereof, in combination with aCOX-2 inhibitor, in the manufacture of a medicament, for the treatmentor prophylaxis of inflammatory diseases.
 9. A method of treating, orreducing the risk of, human diseases or conditions in which inhibitionof nitric oxide synthase activity is beneficial which comprisesadministering a therapeutically effective amount of a compound offormula (I), as defined in claim 1, or a pharmaceutically acceptablesalt, enantiomer or racemate thereof, to a person suffering from, or atincreased risk of, such diseases or conditions.
 10. A method oftreatment according to claim 9 in which it is predominantly induciblenitric oxide synthase that is inhibited.
 11. A method of treating, orreducing the risk of, inflammatory disease in a person suffering from,or at risk of, said disease, wherein the method comprises administeringto the person a therapeutically effective amount of a compound offormula (I), as defined in claim 1, or a pharmaceutically acceptablesalt, enantiomer or racemate thereof.
 12. The method of treatment asclaimed in claim 11 wherein the disease is inflammatory bowel disease.13. The method of treatment as claimed in claim 11 wherein the diseaseis rheumatoid arthritis.
 14. The method of treatment as claimed in claim11 wherein the disease is osteoarthritis.
 15. A method of treating, orreducing the risk of, pain in a person suffering from, or at risk of,said condition, wherein the method comprises administering to the persona therapeutically effective amount of a compound of formula (I), asdefined in claim 1, or a pharmaceutically acceptable salt, enantiomer orracemate thereof.
 16. A method of treating, or reducing the risk of,inflammatory disease in a person suffering from, or at risk of, saiddisease, wherein the method comprises administering to the person atherapeutically effective amount of a combination of a compound offormula (I), as defined in claim 1, or a pharmaceutically acceptablesalt, enantiomer or racemate thereof, with a COX-2 inhibitor.
 17. Apharmaceutical formulation comprising a therapeutically effective amountof a compound of formula (I), or a pharmaceutically acceptable salt,enantiomer or racemate thereof, in admixture with a pharmaceuticallyacceptable adjuvant, diluent or carrier, for use in the treatment orprophylaxis of diseases or conditions in which inhibition of nitricoxide synthase activity is beneficial.
 18. A pharmaceutical formulationcomprising a therapeutically effective amount of a compound of formula(I), or a pharmaceutically acceptable salt, enantiomer or racematethereof, in admixture with a pharmaceutically acceptable adjuvant,diluent or carrier, for use in the treatment or prophylaxis of diseasesor conditions in which inhibition of the inducible isoform of the enzymenitric oxide synthase activity is beneficial.
 19. A pharmaceuticalformulation according to claim 17 for use in the treatment orprophylaxis of inflammatory disease.
 20. A compound of formula (Ia)

wherein X and Y independently represent C1 to 4 alkyl, C1 to 4 alkoxy,halogen, CF₃, OCF₃, CN, C≡CH, S(O)_(m)CH₃, S(O)_(p)CF₃, NO₂ or NHCHO; mand p independently represent an integer 0, 1 or 2; Z represents H orfluoro; V represents O; W represents phenyl or a five or six memberedaromatic heterocyclic ring containing 1 to 3 heteroatoms independentlyselected from O, S and N; said phenyl or aromatic heterocyclic ringbeing optionally substituted by one or more substituents selectedindependently from halogen, C1 to 4 alkyl, C1 to 4 alkoxy, OH, CN, NO₂or NR⁴R⁵; said alkyl or alkoxy group being optionally furthersubstituted by one or more fluorine atoms; R¹ and R² independentlyrepresent H, C1 to 4 alkyl or C3 to 6 cycloalkyl; said alkyl group beingoptionally substituted by C1 to 4 alkoxy, halogen, hydroxy, NR⁶R⁷,phenyl or a five or six membered aromatic or saturated heterocyclic ringcontaining 1 to 3 heteroatoms independently selected from O, S and N;said phenyl or aromatic heterocyclic ring being optionally furthersubstituted by halogen, C1 to 4 alkyl, C1 to 4 alkoxy, CF₃, OCF₃, CN orNO₂; or the group NR¹R² together represents a 4 to 8 membered saturatedazacyclic ring optionally incorporating one further heteroatom selectedfrom O, S or NR⁸; said ring being substituted by OH or by C1 to 4 alkylsubstituted by C1 to 4 alkoxy, OH or NR⁹R¹⁰; or the group NR¹R² togetherrepresents part of a five membered aromatic azacyclic ring optionallyincorporating one further N atom; R⁴, R⁵R⁶, R⁷, R⁹ and R¹⁰ independentlyrepresent H or C1 to 4 alkyl; R⁸ represents H or C1 to 6 alkyl; saidalkyl group being optionally substituted by C1 to 4 alkoxy, OH, NR¹¹R¹²,phenyl or a five or six membered aromatic or saturated heterocyclic ringcontaining 1 to 3 heteroatoms independently selected from O, S and N;said phenyl or aromatic heterocyclic ring being optionally furthersubstituted by halogen, C1 to 4 alkyl, C1 to 4 alkoxy, CF₃, OCF₃, CN orNO₂; R¹¹ and R¹² independently represent H or C1 to 4 alkyl; or apharmaceutically acceptable salt, enantiomer or racemate thereof, withthe proviso that when W represents optionally substituted phenyl,thienyl, furanyl or pyrrolyl and R¹ represents H, C1 to 4 alkyl or C3 to6 cycloalkyl optionally substituted by C1 to 4 alkoxy, then R² does notrepresent H, C1 to 4 alkyl or C3 to 6 cycloalkyl optionally substitutedby C1 to 4 alkoxy; and with the proviso that when W represents thiazolylor pyridyl, then either Z represents F; or at least one of X and Yrepresents CN; or R¹ and R² do not independently represent H or CH₃. 21.A compound of formula (Ia), according to claim 20, wherein X and Yindependently represent Br, Cl, CH₃, CF₃ or CN.
 22. A compound offormula (Ia), according to claim 20, wherein W represents an optionallysubstituted five or six membered aromatic heterocyclic ring containing 1to 3 heteroatoms independently selected from O, S and N.
 23. A compoundof formula (Ia), according to claim 20, wherein R¹ and R² independentlyrepresent H or methyl.
 24. A compound of formula (Ia), according toclaim 20, which is:2-[[(3R)-3-(2,5-dichlorophenoxy)-3-(2-thienyl)propyl]amino]ethanol;4-chloro-2-{[(1R)-3-(4-hydroxy-1-piperidinyl)-1-phenylpropyl]oxy}-benzonitrile;4-chloro-2-{[(1R)-3-[(2-hydroxyethyl)methylamino]-1-phenylpropyl]oxy}-benzonitrile;4-chloro-2-{[(1R)-3-[(3R)-3-hydroxypyrrolidinyl]-1-phenylpropyl]oxy}-benzonitrile;4-chloro-2-{[(1R)-3-[(3S)-3-hydroxypyrrolidinyl]-1-phenylpropyl]oxy}-benzonitrile;4-chloro-5-fluoro-2-[3-methylamino)-1-(2-pyrimidinyl)propoxy]benzonitrile;4-chloro-5-fluoro-2-({(1R)-3-[(3-hydroxypropyl)amino]-1-phenylpropyl}oxy)benzonitrile;4-chloro-5-fluoro-2-[[(1R)-1-(3-furanyl)-3-(3-hydroxypropyl)amino]propyl]oxy}benzonitrile;4-chloro-5-fluoro-2-{[(1R)-3-[(3-hydroxypropyl)amino]-1-(3-thienyl)propyl]oxy}benzonitrile;4-chloro-5-fluoro-2-({(1R)-3-[(3-hydroxypropyl)amino]-1-phenylpropyl}oxy)benzonitrile;4-bromo-5-fluoro-2-({(1R)-1-(3-furanyl)-3-[(3-hydroxypropyl)amino]propyl}oxy)benzonitrile;4-bromo-5-fluoro-2-{[(1R)-3-[(3-hydroxypropyl)amino]-1-(3-thienyl)propyl]oxy}benzonitrile;4-chloro-5-fluoro-2-[[(1R)-3-[[(5-methylpyrazinyl)methyl]amino]-1-phenylpropyl]oxy]benzonitrile;4-chloro-5-fluoro-2-[[(1R)-3-[(1H-imidazol-2-ylmethyl)amino]-1-phenylpropyl]oxy]benzonitrile;4-chloro-2-[[(1R)-3-[[2-(dimethylamino)ethyl]amino]-1-phenylpropyl]oxy]-5-fluorobenzonitrile;4-chloro-5-fluoro-2-[[(1R)-3-[[2-(4-morpholinyl)ethyl]amino]-1-phenylpropyl]oxy]benzonitrile;4-chloro-5-fluoro-2-[[(1R)-3-[[2-(1H-imidazol-1-yl)ethyl]amino]-1-phenylpropyl]oxy]benzonitrile;4-chloro-5-fluoro-2-[[(1R)-3-[[2-(1H-imidazol-4-yl)ethyl]amino]-1-phenylpropyl]oxy]benzonitrile;4-chloro-5-fluoro-2-[[(1R)-3-[(2-hydroxyethyl)amino]-1-phenylpropyl]oxy]benzonitrile;2-[[(1R)-3-[(2-aminoethyl)amino]-1-phenylpropyl]oxy]-4-chloro-5-fluorobenzonitrile;4-chloro-5-fluoro-2-[[(1R)-1-phenyl-3-[(3,3,3-trifluoropropyl)amino]propyl]oxy]benzonitrile;2-{[(1R)-3-amino-1-(2-thiazolyl)propyl]oxy}-4-chlorobenzonitrile;4-chloro-2-{[(1R)-3-(methylamino)-1-(2-thiazolyl)propyl]oxy}benzonitrile;2-[3-amino-1-(2-oxazolyl)propoxy]-4-chlorobenzonitrile;2-{[(1R)-3-amino-1-(2-thiazolyl)propyl]oxy}-4-chlorobenzonitrile;γ-(2,5-dichlorophenoxy)-2-oxazolepropanamine;2-[[-3-amino-1-(3-pyridinyl)propyl]oxy]-4-chloro-5-fluorobenzonitrile;4-chloro-5-fluoro-2-[3-(methylamino)-1-(3-pyridinyl)propoxy]benzonitrile;2-[3-amino-1-(6-methoxy-2-pyridinyl)propoxy]-4-chloro-5-fluorobenzonitrile;2-[3-amino-1-(1,6-dihydro-6-oxo-2-pyridinyl)propoxy]-4-chloro-5-fluorobenzonitrile;2-[3-amino-1-(6-bromo-3-pyridinyl)propoxy]-4-chlorobenzonitrile;2-[[3-amino-1-(5-isoxazolyl)propyl]oxy]-4-chlorobenzonitrile;4-chloro-2-[3-[(2-hydroxyethyl)amino]-1-(5-isoxazolyl)propoxy]benzonitrile;(R)-γ-(2,5-dichlorophenoxy)-5-isoxazolepropanamine;4-chloro-5-fluoro-2-[[(1R)-3-[(2-hydroxyethyl)amino]-1-(3-thienyl)propyl]oxy]benzonitrile;2-[[(1R)-3-[(2-aminoethyl)amino]-1-(3-thienyl)propyl]oxy]-4-chloro-5-fluoro-benzonitrile;4-chloro-2-[3-methylamino)-1-(2-thiazolyl)propoxy]-benzonitrile;2-[[(1R)-3-amino-1-(2-thiazolyl)propyl]oxy]-4-chloro-5-fluoro-benzonitrile;4-chloro-5-fluoro-2-{[(1R)-3-[(2-fluoroethyl)amino]-1-phenylpropyl]oxy}benzonitrile;3-[[(3R)-3-(2,5-dichlorophenoxy)-3-phenylpropyl]amino]-1-propanol;1-[(3R)-3-(2,5-dichlorophenoxy)-3-phenylpropyl]-4-piperidinemethanol;N-[(3R)-3-(2,5-dichlorophenoxy)-3-phenylpropyl]-2-thiophenemethanamine;N-[(3R)-3-(2,5-dichlorophenoxy)-3-phenylpropyl]-5-methyl-2-furanmethanamine;5-fluoro-2-[[(1R)-3-[(2-hydroxyethyl)amino]-1-(3-isoxazolyl)propyl]oxy]-4-methyl-benzonitrile;2-[[(1R)-3-amino-1-(3-isoxazolyl)propyl]oxy]-5-fluoro-4-methyl-benzonitrile;4-chloro-2-[[(1R)-3-[(1,1-dimethylethyl)amino]-1-(3-isoxazolyl)propyl]oxy]benzonitrile;2-[[(1R)-3-amino-1-(3-isoxazolyl)propyl]oxy]-4-chloro-benzonitrile;2-[[(1R)-3-amino-1-(3-isoxazolyl)propyl]oxy]-4-chloro-5-fluoro-benzonitrile;(R)-γ-(2,5-dichlorophenoxy)-3-isoxazolepropanamine;2-[[(1R)-3-amino-1-(3-isoxazolyl)propyl]oxy]-4-(trifluoromethyl)-benzonitrile;2-[[(1R)-3-amino-1-(5-methyl-3-isoxazolyl)propyl]oxy]-4-chloro-5-fluoro-benzonitrile;or pharmaceutically acceptable salts, enantiomers or racemates therof.25. A compound of formula (Ia), according to any one of claims 20 to 24,or a pharmaceutically acceptable salt, enantiomer or racemate thereof,for use as a medicament.
 26. A pharmaceutical composition comprising acompound of formula (Ia) according to any one of claims 20 to 24, or apharmaceutically acceptable salt, enantiomer or racemate thereof, inadmixture with a pharmaceutically acceptable adjuvant, diluent orcarrier.
 27. A process for the preparation of a compound of formula(Ia), as defined in any one of claims 20 to 24, or a pharmaceuticallyacceptable salt, enantiomer or racemate thereof, wherein the processcomprises: (a) reaction of a compound of formula (II)

wherein X, Y, V and Z are as defined in claim 20, with a compound offormula (III)

wherein W, R¹ and R² are as defined in claim 20; or (b) reaction of acompound of formula (IV)

wherein X, Y and Z are as defined in claim 20 and L¹ represents aleaving group, with a compound of formula (V)

wherein R¹, R², V and W are as defined in claim 20; or (c) reaction of acompound of formula (VI)

wherein X, Y, V, W and Z are as defined in claim 20 and L² is a leavinggroup, with a compound of formula (VII) HNR¹R²   (VII) wherein R¹ and R²are as defined in claim 20; or (d) reaction of a compound of formula(II)

wherein X, Y, V and Z are as defined in claim 20, with a compound offormula (VIII)

wherein R¹, R² and W are as defined in claim 20 and L³ is a leavinggroup; or (e) reduction of a compound of formula (IX)

wherein X, Y, V, W and Z are as defined in claim 20 and G represents agroup that upon reduction is converted into a group NR¹R²; and wherenecessary converting the resultant compound of formula (Ia), or anothersalt thereof, into a pharmaceutically acceptable salt thereof; orconverting the resultant compound of formula (Ia) into a furthercompound of formula (Ia); and where desired converting the resultantcompound of formula (Ia) into an optical isomer thereof.